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Ghaffari MK, Rafati A, Karbalaei N, Haghani M, Nemati M, Sefati N, Namavar MR. The effect of intra-nasal co-treatment with insulin and growth factor-rich serum on behavioral defects, hippocampal oxidative-nitrosative stress, and histological changes induced by icv-STZ in a rat model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4833-4849. [PMID: 38157024 DOI: 10.1007/s00210-023-02899-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/09/2023] [Indexed: 01/03/2024]
Abstract
Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus.
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Affiliation(s)
- Mahdi Khorsand Ghaffari
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Rafati
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Narges Karbalaei
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoud Haghani
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Nemati
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Niloofar Sefati
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Reza Namavar
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Khoramipour K, Rezaei MH, Moslemizadeh A, Hosseini MS, Ebrahimnezhad N, Bashiri H. Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2024; 20:9. [PMID: 38702776 PMCID: PMC11067136 DOI: 10.1186/s12993-024-00235-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 04/08/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aβ) and Tau were also assessed using Western blot. RESULTS An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.
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MESH Headings
- Animals
- Female
- Hippocampus/metabolism
- tau Proteins/metabolism
- Rats
- Physical Conditioning, Animal/physiology
- Physical Conditioning, Animal/methods
- Physical Conditioning, Animal/psychology
- Anxiety/therapy
- Anxiety/psychology
- Anxiety/metabolism
- Amyloid beta-Peptides/metabolism
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/psychology
- Diabetes Mellitus, Experimental/therapy
- High-Intensity Interval Training/methods
- Maze Learning/physiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/psychology
- Diabetes Mellitus, Type 2/therapy
- Behavior, Animal/physiology
- Diet, High-Fat/adverse effects
- Rats, Sprague-Dawley
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Affiliation(s)
- Kayvan Khoramipour
- Student Research Committee, School of medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Hossein Rezaei
- Department of Exercise Physiology, Faculty of Physical Education, Shahid Bahonar University, Kerman, Iran
| | | | - Mahdieh Sadat Hosseini
- Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Narjes Ebrahimnezhad
- Department of Sports Science, Faculty of Educational Sciences and Psychology, Sistan and Baluchestan University, Zahedan, Iran
| | - Hamideh Bashiri
- Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
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Palazzo E, Marabese I, Boccella S, Belardo C, Pierretti G, Maione S. Affective and Cognitive Impairments in Rodent Models of Diabetes. Curr Neuropharmacol 2024; 22:1327-1343. [PMID: 38279738 PMCID: PMC11092917 DOI: 10.2174/1570159x22666240124164804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 01/28/2024] Open
Abstract
Diabetes and related acute and long-term complications have a profound impact on cognitive, emotional, and social behavior, suggesting that the central nervous system (CNS) is a crucial substrate for diabetic complications. When anxiety, depression, and cognitive deficits occur in diabetic patients, the symptoms and complications related to the disease worsen, contributing to lower quality of life while increasing health care costs and mortality. Experimental models of diabetes in rodents are a fundamental and valuable tool for improving our understanding of the mechanisms underlying the close and reciprocal link between diabetes and CNS alterations, including the development of affective and cognitive disorders. Such models must reproduce the different components of this pathological condition in humans and, therefore, must be associated with affective and cognitive behavioral alterations. Beyond tight glycemic control, there are currently no specific therapies for neuropsychiatric comorbidities associated with diabetes; animal models are, therefore, essential for the development of adequate therapies. To our knowledge, there is currently no review article that summarizes changes in affective and cognitive behavior in the most common models of diabetes in rodents. Therefore, in this review, we have reported the main evidence on the alterations of affective and cognitive behavior in the different models of diabetes in rodents, the main mechanisms underlying these comorbidities, and the applicable therapeutic strategy.
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Affiliation(s)
- Enza Palazzo
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Ida Marabese
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Serena Boccella
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Carmela Belardo
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Gorizio Pierretti
- Department of Plastic Surgery, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
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Taha M, Mahmoud ME, Al-Kushi AG, Sarhan A, Abdelbagi O, Baokbah TAS, Babateen O, El-Shenbaby I, Qusty NF, Elazab ST. Anxiolytic and antidepressant like effects of Zamzam water in STZ-induced diabetic rats, targeting oxidative stress, neuroinflammation, BDNF/ERK/CREP pathway with modulation of hypothalamo-pituitary-adrenal axis. Front Neurosci 2023; 17:1265134. [PMID: 38105928 PMCID: PMC10722298 DOI: 10.3389/fnins.2023.1265134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/18/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction Recent studies have reported a strong relationship between diabetes and anxiety- and depression-like behaviors; however, there is a lack of information on the underlying pathophysiology. Alkaline Zamzam water (ZW), which is rich in several trace elements, has neuroprotective properties. This study aimed to investigate the anxiolytic and antidepressant effects of ZW against diabetes-induced behavioral changes and shed light on the possible underlying mechanisms. Methods Forty-eight rats were divided into four experimental groups (n = 12): group I (control group), group II (Zamzam water group), group III (diabetic group), and group IV (diabetic + Zamzam water group). Diabetes was induced by an intraperitoneal injection of 60 mg/kg streptozotocin (STZ). At the end of the experiment, the forced swimming test (FST) was used to assess depression-like effects. The elevated plus maze test (EPMT) and open field test (OFT) were performed to evaluate anxiety-like behavior. Blood levels of the hypothalamic-pituitary-adrenal (HPA) axis were measured, and prefrontal cortex and hippocampal tissue samples were removed for histological, immunohistochemical, ELISA, and Q-PCR analyses. Results ZW significantly decreased the immobility time in the FST, indicating an antidepressant effect (p < 0.001). Additionally, ZW significantly improved the OFT and open field entry (OFE) percentages in the EPMT, increasing center crossing and decreasing grooming and fecal boli in the OFT. This indicated an anxiolytic-like effect in diabetic rats with histological improvement. Interestingly, ZW significantly increased prefrontal cortical and hippocampal levels of antioxidant enzymes and the Nrf2/HO-1 pathway. It also modulated the HPA axis by increasing cortisol and corticotropin-releasing hormone (CRH) levels, with a decrease in ACTH and an increase in monoamine neurotransmitters. Furthermore, diabetic rats that received ZW showed a decrease in the inflammatory markers TNF-α and GFAP by immunohistochemistry and in the mRNA levels of NFκB, IL-1β, and IL6. In addition, ZW downregulated the expression of the BDNF/ERK2/CREP pathway. Conclusion Our results suggested a neuroprotective effect of ZW against diabetes-induced anxiety- and depression-like behaviors and explored the underlying mechanisms. These findings suggest a promising therapeutic strategy for patients with diabetes who experience anxiety and depression.
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Affiliation(s)
- Medhat Taha
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Anatomy, Al-Qunfudah Medical College, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia
| | - Mohamed Ezzat Mahmoud
- Histology Department, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Abdullah G. Al-Kushi
- Department of Human Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah, Makkah, Saudi Arabia
| | - Anas Sarhan
- Department of Internal Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Omer Abdelbagi
- Department of Pathology, Qunfudah Faculty of Medicine, Umm-Al-Qura University, Al-Qunfudah, Saudi Arabia
| | - Tourki A. S. Baokbah
- Department of Medical Emergency Services, College of Health Sciences-AlQunfudah, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia
| | - Omar Babateen
- Department of Physiology, Faculty of Medicine, Umm Al-Qura University, Makkah, Makkah, Saudi Arabia
| | - Ibrahim El-Shenbaby
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Naeem F. Qusty
- Medical Laboratories Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sara T. Elazab
- Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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Lin JY, Tsai BCK, Kao HC, Chiang CY, Chen YA, Chen WST, Ho TJ, Yao CH, Kuo WW, Huang CY. Neuroprotective Effects of Probiotic Lactobacillus reuteri GMNL-263 in the Hippocampus of Streptozotocin-Induced Diabetic Rats. Probiotics Antimicrob Proteins 2023; 15:1287-1297. [PMID: 36044175 DOI: 10.1007/s12602-022-09982-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2022] [Indexed: 11/27/2022]
Abstract
Diabetes-related brain complications have been reported in clinical patients and experimental models. The objective of the present study was to investigate the neuroprotective mechanisms of Lactobacillus reuteri GMNL-263 in streptozotocin (STZ)-induced diabetic rats. In this study, three different groups, namely control group, STZ-induced (55 mg/kg streptozotocin intraperitoneally) diabetic rats (DM), and DM rats treated with Lactobacillus reuteri GMNL-263 (1 × 109 CFU/rat/day), were utilized to study the protective effect of GMNL-263 in the hippocampus of STZ-induced diabetic rats. The results demonstrated that GMNL-263 attenuated diabetes-induced hippocampal damage by enhancing the cell survival pathways and repressing both inflammatory and apoptotic pathways. Histopathological analysis revealed that GMNL-263 prevented structural changes in the hippocampus in the DM group and decreased the level of inflammation and apoptosis in the hippocampus of DM rats. The IGF1R cell survival signaling pathway also improved after GMNL-263 treatment. These results indicate that probiotic GMNL-263 exerts beneficial effects in the brain of diabetic rats and has potential ability for clinical application.
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Affiliation(s)
- Jing-Ying Lin
- Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Bruce Chi-Kang Tsai
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Hui-Chuan Kao
- Department of Public Health, Tzu Chi University, Hualien, Taiwan
| | - Chien-Yi Chiang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yun-An Chen
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - William Shao-Tsu Chen
- Department of Psychiatry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Medicine, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Tsung-Jung Ho
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Chun-Hsu Yao
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Biomaterials Translational Research Center, China Medical University Hospital, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
- Center of General Education, Tzu Chi University of Science and Technology, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
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Ventura-Aquino E, Paredes RG. Being friendly: paced mating for the study of physiological, behavioral, and neuroplastic changes induced by sexual behavior in females. Front Behav Neurosci 2023; 17:1184897. [PMID: 37840548 PMCID: PMC10568070 DOI: 10.3389/fnbeh.2023.1184897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 09/14/2023] [Indexed: 10/17/2023] Open
Abstract
Paced mating in rats is an experimental condition that allows the evaluation of sexual behavior in a way that closely resembles what occurs in seminatural and natural conditions enabling the female to control the rate of the sexual interaction. In conventional non-paced mating tests, females cannot escape from male approaches, which may lead to an unrewarding overstimulation. Paced mating is an alternative laboratory procedure that improves animal welfare and has a higher ethological relevance. The use of this procedure contributed to the identification of physiological and behavioral factors that favor reproduction. Paced mating includes motivational and behavioral components differentiating quantitative and qualitative characteristics that are critical for the induction of the rewarding properties of mating. These positive consequences ensure that the behavior will be repeated, favoring the species' survival. Sexual reward is an immediate consequence of paced mating, mediated mainly by the endogenous opioid system. Paced mating also induces long-lasting neuroplastic changes, including gene expression, synthesis of proteins, and neurogenesis in sex-relevant brain areas. The interest in paced mating is growing since the complexity of its elements and consequences at different levels in a laboratory setting resembles what occurs in natural conditions. In this review, we analyze the classic studies and recent publications demonstrating the advantages of using paced mating to evaluate different aspects of sexual behavior in females.
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Affiliation(s)
- Elisa Ventura-Aquino
- Escuela Nacional de Estudios Superiores, Unidad Juriquilla, Universidad Nacional Autónoma de México, Querétaro, Mexico
| | - Raúl G. Paredes
- Escuela Nacional de Estudios Superiores, Unidad Juriquilla, Universidad Nacional Autónoma de México, Querétaro, Mexico
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico
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Kisielinski K, Wagner S, Hirsch O, Klosterhalfen B, Prescher A. Possible toxicity of chronic carbon dioxide exposure associated with face mask use, particularly in pregnant women, children and adolescents - A scoping review. Heliyon 2023; 9:e14117. [PMID: 37057051 PMCID: PMC9981272 DOI: 10.1016/j.heliyon.2023.e14117] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction During the SARS-CoV-2-pandemic, face masks have become one of the most important ubiquitous factors affecting human breathing. It increases the resistance and dead space volume leading to a re-breathing of CO2. So far, this phenomenon and possible implications on early life has not been evaluated in depth. Method As part of a scoping review, literature was systematically reviewed regarding CO2 exposure and facemask use. Results Fresh air has around 0.04% CO2, while wearing masks more than 5 min bears a possible chronic exposure to carbon dioxide of 1.41% to 3.2% of the inhaled air. Although the buildup is usually within the short-term exposure limits, long-term exceedances and consequences must be considered due to experimental data. US Navy toxicity experts set the exposure limits for submarines carrying a female crew to 0.8% CO2 based on animal studies which indicated an increased risk for stillbirths. Additionally, mammals who were chronically exposed to 0.3% CO2 the experimental data demonstrate a teratogenicity with irreversible neuron damage in the offspring, reduced spatial learning caused by brainstem neuron apoptosis and reduced circulating levels of the insulin-like growth factor-1. With significant impact on three readout parameters (morphological, functional, marker) this chronic 0.3% CO2 exposure has to be defined as being toxic. Additional data exists on the exposure of chronic 0.3% CO2 in adolescent mammals causing neuron destruction, which includes less activity, increased anxiety and impaired learning and memory. There is also data indicating testicular toxicity in adolescents at CO2 inhalation concentrations above 0.5%. Discussion There is a possible negative impact risk by imposing extended mask mandates especially for vulnerable subgroups. Circumstantial evidence exists that extended mask use may be related to current observations of stillbirths and to reduced verbal motor and overall cognitive performance in children born during the pandemic. A need exists to reconsider mask mandates.
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Affiliation(s)
- Kai Kisielinski
- Independent Researcher, Surgeon, Private Practice, 40212 Düsseldorf, Germany
| | - Susanne Wagner
- Non Clinical Expert, Veterinarian, Wagner MSL Management, 15831 Mahlow, Germany
| | - Oliver Hirsch
- Department of Psychology, FOM University of Applied Sciences, 57078 Siegen, Germany
| | | | - Andreas Prescher
- Institute of Molecular and Cellular Anatomy (MOCA), 52074 Aachen, Germany
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Pereira ADS, Miron VV, Castro MFV, Bottari NB, Assmann CE, Nauderer JN, Bissacotti BF, Mostardeiro VB, Stefanello N, Baldissarelli J, Palma TV, Morsch VMM, Schetinger MRC. Neuromodulatory effect of the combination of metformin and vitamin D 3 triggered by purinergic signaling in type 1 diabetes induced-rats. Mol Cell Endocrinol 2023; 563:111852. [PMID: 36657632 DOI: 10.1016/j.mce.2023.111852] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
Several studies have indicated the vitamin D deficiency in the development of macro- and microvascular complications of diabetes mellitus (DM) including DM-related cognitive dysfunction. The purinergic system plays an important role in the modulation of a variety of mechanisms, including neuroinflammation, plasticity, and cell-cell communication. In addition, purines, their receptors, and enzymes can regulate the purinergic axis at different levels in type 1 DM (T1DM). This study evaluated the effects of vitamin D3 alone or in combination with metformin in the behavioral performance of streptozotocin-induced T1DM rats. The effects of this combination on the metabolism of ATP and ADP were also studied by NTPDase (CD39), AMP by 5'-nucleotidase (CD73), and adenosine by adenosine deaminase (E-ADA) in the brain and peripheral lymphocytes of type 1 diabetic STZ-induced rats. The results showed that anxiety and memory loss from the DM condition reverted after 30 days of vitamin D3 treatment. Furthermore, the DM state affected systemic enzymes, with no effect on the central enzymes hydrolyzing extracellular nucleotides and nucleosides. Vitamin D3 treatment positively regulated ectonucleotidase (NTPDase and 5'-nucleotidase) activity, E-ADA, and the purinergic receptors as a mechanism to prevent oxidative damage in the cerebral cortex of T1DM rats. A neuroprotector effect of vitamin D3 through adenosine signaling was also observed, by regulating A1 and A2A receptors proteins levels. The present findings suggest that purinergic signaling through vitamin D3 modulation may be a novel alternative strategy for T1DM treatment, and may compensate for the negative changes in the central nervous system.
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Affiliation(s)
- Aline da Silva Pereira
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil.
| | - Vanessa Valéria Miron
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Milagros Fanny Vera Castro
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Nathieli Bianchin Bottari
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Charles Elias Assmann
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Jelson Norberto Nauderer
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Bianca Fagan Bissacotti
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Vitor Bastianello Mostardeiro
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Naiara Stefanello
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Jucimara Baldissarelli
- Departamento de Fisiologia e Farmacologia, Universidade Federal de Pelotas (UFPEL), Pelotas, RS, Brazil
| | - Taís Vidal Palma
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Vera Maria Melchiors Morsch
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Maria Rosa Chitolina Schetinger
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil.
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Arjunan A, Sah DK, Woo M, Song J. Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome. Cell Biosci 2023; 13:16. [PMID: 36691085 PMCID: PMC9872444 DOI: 10.1186/s13578-023-00966-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
Neurodegenerative disorders are accompanied by neuronal degeneration and glial dysfunction, resulting in cognitive, psychomotor, and behavioral impairment. Multiple factors including genetic, environmental, metabolic, and oxidant overload contribute to disease progression. Recent evidences suggest that metabolic syndrome is linked to various neurodegenerative diseases. Metabolic syndrome (MetS) is known to be accompanied by symptoms such as hyperglycemia, abdominal obesity, hypertriglyceridemia, and hypertension. Despite advances in knowledge about the pathogenesis of neurodegenerative disorders, effective treatments to combat neurodegenerative disorders caused by MetS have not been developed to date. Insulin growth factor-1 (IGF-1) deficiency has been associated with MetS-related pathologies both in-vivo and in-vitro. IGF-1 is essential for embryonic and adult neurogenesis, neuronal plasticity, neurotropism, angiogenesis, metabolic function, and protein clearance in the brain. Here, we review the evidence for the potential therapeutic effects of IGF-1 in the neurodegeneration related to metabolic syndrome. We elucidate how IGF-1 may be involved in molecular signaling defects that occurs in MetS-related neurodegenerative disorders and highlight the importance of IGF-1 as a potential therapeutic target in MetS-related neurological diseases.
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Affiliation(s)
- Archana Arjunan
- grid.14005.300000 0001 0356 9399Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-Do 58128 Republic of Korea
| | - Dhiraj Kumar Sah
- grid.14005.300000 0001 0356 9399Department of Biochemistry, Chonnam National University Medical School, Hwasun, 58128 Republic of Korea ,grid.14005.300000 0001 0356 9399BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun, 58128 Republic of Korea
| | - Minna Woo
- grid.17063.330000 0001 2157 2938Division of Endocrinology and Metabolism, University Health Network and and Banting and Best Diabetes Centre, University of Toronto, Toronto, ON Canada
| | - Juhyun Song
- grid.14005.300000 0001 0356 9399Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-Do 58128 Republic of Korea ,grid.14005.300000 0001 0356 9399BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun, 58128 Republic of Korea
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10
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Zhang Y, Sun Q, Li H, Wang D, Wang Y, Wang Z. Lower serum insulin-like growth factor 1 concentrations in patients with chronic insomnia disorder. Front Psychiatry 2023; 14:1102642. [PMID: 37151979 PMCID: PMC10160412 DOI: 10.3389/fpsyt.2023.1102642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
Objectives Insulin-like growth factor 1 (IGF-1) is a crucial neurotrophin that is produced in the brain and periphery and may play an important role in insomnia and mood disorders. We aimed to analyze its serum concentrations in patients with chronic insomnia disorder (CID). Methods Patients with CID were enrolled in this study and divided into the CID group [Generalized Anxiety Disorder-7 (GAD-7) score < 10] and the CID with anxiety group (GAD-7 score ≥ 10). Age-and sex-matched healthy volunteers were recruited as controls. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and the GAD-7 and the Patient Health Questionnaire-9 to assess emotional status. All subjects were monitored via polysomnography, and the serum IGF-1 concentrations in their peripheral blood were detected via enzyme-linked immunosorbent assays. Results We enrolled 65 patients with CID (of whom 35 had anxiety) and 36 controls. The PSQI score and IGF-1 concentration in the CID and CID with anxiety groups were higher than those in the control group. The apparent difference in IGF-1 concentration between the CID and CID with anxiety groups was not statistically significant. The IGF-1 concentration in patients with CID was linearly correlated with the GAD-7 score, PSQI score, and stage 3 non-rapid eye movement (stage N3) time. Conclusion The serum IGF-1 concentration in patients with CID was lower than that of participants without CID, negatively correlated with anxiety score and sleep quality, and positively correlated with stage N3 time.
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11
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Orumiyehei A, Khoramipour K, Rezaei MH, Madadizadeh E, Meymandi MS, Mohammadi F, Chamanara M, Bashiri H, Suzuki K. High-Intensity Interval Training-Induced Hippocampal Molecular Changes Associated with Improvement in Anxiety-like Behavior but Not Cognitive Function in Rats with Type 2 Diabetes. Brain Sci 2022; 12:1280. [PMID: 36291214 PMCID: PMC9599079 DOI: 10.3390/brainsci12101280] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/01/2022] [Accepted: 09/16/2022] [Indexed: 09/29/2023] Open
Abstract
(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of VMax, 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.
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Affiliation(s)
- Amin Orumiyehei
- Toxicology Research Center, Aja University of Medical Sciences, Tehran 1411718541, Iran
| | - Kayvan Khoramipour
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman 7616914115, Iran
| | - Maryam Hossein Rezaei
- Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Bahonar University, Kerman 7616913439, Iran
| | - Elham Madadizadeh
- Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Bahonar University, Kerman 7616913439, Iran
| | - Manzumeh Shamsi Meymandi
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman 7616914115, Iran
| | | | - Mohsen Chamanara
- Toxicology Research Center, Aja University of Medical Sciences, Tehran 1411718541, Iran
- Department of Pharmacology, School of Medicine, Aja University of Medical Sciences, Tehran 1411718541, Iran
| | - Hamideh Bashiri
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman 7616914115, Iran
| | - Katsuhiko Suzuki
- Faculty of Sport Sciences, Institute of Sports Nutrition, Waseda University, Saitama 359-1192, Japan
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12
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Sesamin alleviates diabetes-associated behavioral deficits in rats: The role of inflammatory and neurotrophic factors. Int Immunopharmacol 2021; 92:107356. [PMID: 33440305 DOI: 10.1016/j.intimp.2020.107356] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/23/2020] [Accepted: 12/27/2020] [Indexed: 12/13/2022]
Abstract
Neuroinflammation and loss of neurotrophic support have key roles in the pathophysiology of diabetes-associated behavioral deficits (DABD). Sesamin (Ses), a major lignan of sesame seed and its oil, shows anti-hyperglycemic, anti-oxidative, and neuroprotective effects. The present study was designed to assess the potential protective effects of Ses against DABD and investigate the roles of inflammatory markers and neurotrophic factors in streptozotocin (STZ)-induced diabetic rats. After confirmation of diabetes, Ses (30 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) was administered to rats for eight consecutive weeks. During the eighth-week period of the study, behavioral functions of the animals were evaluated by employing standard behavioral paradigms. Moreover, inflammation status, neurotrophic factors, and histological changes were assessed in the cerebral cortex and hippocampal regions of the rats. The results of behavioral tests showed that STZ-induced diabetes increased anxiety-/depression-like behaviors, decreased locomotor/exploratory activities, and impaired passive avoidance learning and memory. These DABD were accompanied by neuroinflammation, lack of neurotrophic support, and neuronal loss in both cerebral cortex and hippocampus of the rats. Intriguingly, chronic treatment with Ses improved all the above-mentioned diabetes-related behavioral, biochemical, and histological deficits, and in some cases, it was even more effective than insulin therapy. In conclusion, the results suggest that Ses was capable of improving DABD, which might be ascribed, at least partly, to the reduction of blood glucose level, inhibition of neuroinflammation, and potentiation of neurotrophic factors.
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13
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Momeni Z, Neapetung J, Pacholko A, Kiir TAB, Yamamoto Y, Bekar LK, Campanucci VA. Hyperglycemia induces RAGE-dependent hippocampal spatial memory impairments. Physiol Behav 2020; 229:113287. [PMID: 33316294 DOI: 10.1016/j.physbeh.2020.113287] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022]
Abstract
Diabetes is a prevalent metabolic disorder that has long been associated with changes in different regions of the brain, including the hippocampus. Changes in hippocampal synaptic plasticity and subsequent impairment in cognitive functions such as learning and memory, are well documented in animal models of type 1 and type 2 diabetes. It is known that RAGE contributes to peripheral micro- and macro-vascular complications of diabetes. However, it is still unknown if RAGE plays a similar role in the development of CNS complications of diabetes. Therefore, we hypothesize that RAGE contributes to cognitive dysfunction, such as learning and memory impairments, in a mouse model of STZ-induced hyperglycemia. Control and STZ-induced hyperglycemic mice from WT and RAGE-KO groups were used for the behavioral experiments. While STZ-induced hyperglycemia decreased locomotor activity in the open field (OF) test, it did not affect the recognition memory in the novel object recognition (NOR) test in either genotype. Spatial memory, however, was impaired in STZ-induced hyperglycemic mice in WT but not in RAGE-KO group in both the Barnes maze (BM) and the Morris water maze (MWM) tests. Consistently, the RAGE antagonist FPS-ZM1 protected WT STZ-induced hyperglycemic mice from spatial memory impairment in the BM test. Our findings indicate that the parameters associated with locomotor activity and recognition memory were independent of RAGE in STZ-induced hyperglycemic mice. In contrast, the parameters associated with hippocampal-dependent spatial memory were dependent on RAGE expression.
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Affiliation(s)
- Zeinab Momeni
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Joseph Neapetung
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Anthony Pacholko
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Tabitha Achan Bol Kiir
- College of Arts and Science, 9 Campus Drive, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Lane K Bekar
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Verónica A Campanucci
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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14
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Jash K, Gondaliya P, Sunkaria A, Kalia K. MicroRNA-29b Modulates β-Secretase Activity in SH-SY5Y Cell Line and Diabetic Mouse Brain. Cell Mol Neurobiol 2020; 40:1367-1381. [PMID: 32198621 PMCID: PMC11448805 DOI: 10.1007/s10571-020-00823-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/29/2020] [Indexed: 01/18/2023]
Abstract
Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes which may lead to Alzheimer's disease (AD) at a later stage. MicroRNAs are a class of non-coding RNAs that are found to play a role in diabetes. Downregulation of microRNA-29b in diabetes is well reported. Moreover, microRNA-29b is also reported to target the 3' UTR of β-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aβ) in AD via cleavage of amyloid precursor protein (APP). Therefore, the present study was designed to elucidate whether microRNA-29b could be a link between diabetes and dementia. In the in vitro and in vivo diabetic model, we found downregulation of microRNA-29b due to hyperglycemia. After human microRNA-29b treatment, there was a significant improvement in the short-term and spatial memory in diabetic mice. Also, the human microRNA-29b treatment decreased oxidative stress and BACE-1 activity in diabetes. The present findings revealed that the downregulation of microRNA-29b in diabetes could be associated with memory impairment and increased BACE-1 activity. These results would give a future direction to study the role played by microRNAs in diabetes-associated memory impairment and hence aid in the development of therapeutics to treat the same.
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Affiliation(s)
- Kavya Jash
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Piyush Gondaliya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Aditya Sunkaria
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India.
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15
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Pechlivanova D, Krumova E, Kostadinova N, Mitreva-Staleva J, Grozdanov P, Stoynev A. Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats. Metab Brain Dis 2020; 35:527-538. [PMID: 31997264 DOI: 10.1007/s11011-020-00534-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 01/17/2020] [Indexed: 01/13/2023]
Abstract
Diabetes mellitus type 2 (T2DM) is characterized by resistance of insulin receptors and/or inadequate insulin secretion resulting in metabolic and structural complications including vascular diseases, arterial hypertension and different behavioral alterations. We aimed to study the effects of the antihypertensive angiotensin AT1 receptor antagonist losartan on the T2DM-induced changes of exploratory behavior, anxiety, nociception and short term memory in normotensive Wistar and spontaneously hypertensive rats (SHRs). The experimental model of T2DM induced by a combination of high fat diet and streptozotocin, decreased exploratory activity and increased the level of carbonylated proteins in selected brain structures in both strains; as well it increased corticosterone level, pain threshold, anxiety-like behavior, and decline short term memory only in SHRs. Losartan treatment alleviated some of the T2DM- induced metabolic complications, abolished the T2DM-induced hypo activity, and normalized the corticosterone level, carbonylated proteins in brain, nociception and memory. Losartan did not exert effect on the anxiety behavior in both strains. We showed that T2DM exerted more pronounced negative effects on the rats with comorbid hypertension as compared to normotensive rats. Overall effects on the studied behavioral parameters are related to decreased exploration of the new environment, increased anxiety-like behavior, and decline in short-term memory. The systemic sub-chronic treatment with an angiotensin AT1 receptor antagonist losartan ameliorated most of these complications.
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Affiliation(s)
- Daniela Pechlivanova
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113, Sofia, Bulgaria.
| | - Ekaterina Krumova
- Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113, Sofia, Bulgaria
| | - Nedelina Kostadinova
- Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113, Sofia, Bulgaria
| | - Jeny Mitreva-Staleva
- Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113, Sofia, Bulgaria
| | - Petar Grozdanov
- Institute of Microbiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113, Sofia, Bulgaria
| | - Alexander Stoynev
- Department of Pathophysiology, Medical University-Sofia, St. Georgi Sofiyski Str. 1, 1431, Sofia, Bulgaria
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16
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Caliskan H, Akat F, Omercioglu G, Bastug G, Ficicilar H, Bastug M. Aerobic exercise has an anxiolytic effect on streptozotocin‑induced diabetic rats. Acta Neurobiol Exp (Wars) 2020; 80:245-255. [PMID: 32990283 DOI: 10.21307/ane-2020-022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2024]
Abstract
Diabetes is a metabolic disorder characterized by hyperglycemia and impaired insulin secretion or action. Psychological comorbidities, such as depression and anxiety, are more common in people with diabetes. Exercise results in anxiolytic effects, as demonstrated in numerous studies. This study aims to evaluate potential anxiolytic effects of aerobic exercise in streptozotocin (STZ)‑induced diabetes. Male Wistar albino rats (n=40) were randomly divided into four groups of control, exercise, diabetes, and diabetes + exercise. Diabetes was induced with a single i.p. injection of STZ. The incremental load test was applied to exercise groups to determine maximal exercise capacity. Rats exercised on a treadmill at 70% of their maximal capacity for 45 min, five days per week for 12 weeks. On the day after the last exercise session the open field test and elevated plus maze test were carried out. Diabetes caused an increase in anxiety level, reflected in stretch‑attend posture, self‑grooming behaviors, and freezing time, with no significant changes for other behavioral parameters. Training normalized diabetes‑induced deteriorations and also induced a significant anxiolytic effect both on diabetic and non‑diabetic rats. This effect was observed for all behavioral parameters. The results of the open field test and elevated plus maze were consistent. The current results demonstrated a slight increase in anxiety with diabetes and a prominent anxiolytic effect of aerobic exercise. Considering the conflicting results in exercise‑anxiety studies, this study hig hlights the importance of individually designed exercise protocols.
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Affiliation(s)
- Hasan Caliskan
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
- Balikesir University, Faculty of Medicine, Department of Physiology, Balikesir, Turkey
| | - Firat Akat
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey,
| | - Goktug Omercioglu
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
| | - Gulbahar Bastug
- Ankara University, Vocational School of Health Services, Ankara, Turkey
| | - Hakan Ficicilar
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
| | - Metin Bastug
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
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17
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Caliskan H, Akat F, Tatar Y, Zaloglu N, Dursun AD, Bastug M, Ficicilar H. Effects of exercise training on anxiety in diabetic rats. Behav Brain Res 2019; 376:112084. [PMID: 31356829 DOI: 10.1016/j.bbr.2019.112084] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/20/2019] [Accepted: 07/12/2019] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus (DM) is a common health problem, which manifests itself with chronic hyperglycemia and impaired insulin action. The prevalence of anxiety disorders tends to be high in the diabetic population. Exercise has a well-known anxiolytic effect, also demonstrated on rodents, but the effect of exercise on the DM-induced anxiety is still unknown. Female, Wistar albino rats were randomly divided into four groups (n=8) (C; EX; DM; DM+EX). DM was induced by injection (i.p.; 50 mg/kg) of Streptozotocin (STZ). Rats exercised in moderate intensity on the treadmill (15m/min; 5°; 30 min) for 5 weeks. Anxiety-like behavior (ALB) was evaluated by Open field test (OFT) and Elevated Plus Maze (EPM). According to OFT, central time and central entry have increased with in EX but not in DM+EX. There was no difference between C and DM. Central latency time didn't differ among groups. Unsupported rearing increased in both EX and DM+EX. There was no significant decrease in DM. Freezing time was significantly increased in the DM group. Exercise training reduced freezing time both in diabetic and non-diabetic animals. EPM results were similar. Time spent in open arm was increased significantly in exercise groups compared to their sedentary matches, and freezing time data were also parallel to OFT. Our study revealed that diabetes had shown an anxiogenic effect, which was not severe, and it only manifested itself on some behavioral parameters. Exercise training was reduced anxiety-like behavior both in diabetic and non-diabetic rats. However, because of the nature of exercise studies, it is hard to separate the anxiolytic effect of exercise from the alteration of locomotion.
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Affiliation(s)
- Hasan Caliskan
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey; Balikesir University, Faculty of Medicine, Department of Physiology, Balikesir, Turkey
| | - Firat Akat
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey.
| | - Yakup Tatar
- TOBB ETU University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
| | - Nezahet Zaloglu
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
| | - Ali Dogan Dursun
- Atilim University Faculty of Medicine, Department of Physiology Ankara, Turkey
| | - Metin Bastug
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
| | - Hakan Ficicilar
- Ankara University, Faculty of Medicine, Department of Physiology, Ankara, Turkey
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18
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Gokdemir O, Cetinkaya C, Gumus H, Aksu I, Kiray M, Ates M, Kiray A, Baykara B, Baykara B, Sisman AR, Uysal N. The effect of exercise on anxiety- and depression-like behavior of aged rats. Biotech Histochem 2019; 95:8-17. [DOI: 10.1080/10520295.2019.1624825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- O. Gokdemir
- Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
| | - C. Cetinkaya
- School of Sport Sciences and Technology, Dokuz Eylul University, Izmir, Turkey
| | - H. Gumus
- School of Sport Sciences and Technology, Dokuz Eylul University, Izmir, Turkey
| | - I. Aksu
- Division of Behavioral Physiology, Department of Physiology, Dokuz Eylul University, Izmir, Turkey
| | - M. Kiray
- Division of Behavioral Physiology, Department of Physiology, Dokuz Eylul University, Izmir, Turkey
| | - M. Ates
- College of Vocational School of Health Services, School of Medicine Izmir, Dokuz Eylul University, İzmir, Turkey
| | - A. Kiray
- Department of Anatomy, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - B. Baykara
- Department of Child and Adolescent Psychiatry, Dokuz Eylul University, Izmir, Turkey
| | - B. Baykara
- Department of Histology and Embryology, Dokuz Eylul University, Izmir, Turkey
| | - A. R. Sisman
- Department of Biochemistry, Dokuz Eylul University, Izmir, Turkey
| | - N. Uysal
- Division of Behavioral Physiology, Department of Physiology, Dokuz Eylul University, Izmir, Turkey
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Turkson S, Kloster A, Hamilton PJ, Neigh GN. Neuroendocrine drivers of risk and resilience: The influence of metabolism & mitochondria. Front Neuroendocrinol 2019; 54:100770. [PMID: 31288042 PMCID: PMC6886586 DOI: 10.1016/j.yfrne.2019.100770] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/20/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023]
Abstract
The manifestation of risk versus resilience has been considered from varying perspectives including genetics, epigenetics, early life experiences, and type and intensity of the challenge with which the organism is faced. Although all of these factors are central to determining risk and resilience, the current review focuses on what may be a final common pathway: metabolism. When an organism is faced with a perturbation to the environment, whether internal or external, appropriate energy allocation is essential to resolving the divergence from equilibrium. This review examines the potential role of metabolism in the manifestation of stress-induced neural compromise. In addition, this review details the current state of knowledge on neuroendocrine factors which are poised to set the tone of the metabolic response to a systemic challenge. The goal is to provide an essential framework for understanding stress in a metabolic context and appreciation for key neuroendocrine signals.
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Affiliation(s)
- Susie Turkson
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Alix Kloster
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter J Hamilton
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Gretchen N Neigh
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
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Pereira MM, de Morais H, Dos Santos Silva E, Corso CR, Adami ER, Carlos RM, Acco A, Zanoveli JM. The antioxidant gallic acid induces anxiolytic-, but not antidepressant-like effect, in streptozotocin-induced diabetes. Metab Brain Dis 2018; 33:1573-1584. [PMID: 29934859 DOI: 10.1007/s11011-018-0264-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 05/30/2018] [Indexed: 01/12/2023]
Abstract
The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant-like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.
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Affiliation(s)
- Mariana Machado Pereira
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil
| | - Helen de Morais
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil
| | - Eldevan Dos Santos Silva
- Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luís, Km 235 CP 676, São Carlos, SP, CEP 13565-905, Brazil
| | - Claudia Rita Corso
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil
| | - Eliana Rezende Adami
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil
| | - Rose Maria Carlos
- Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luís, Km 235 CP 676, São Carlos, SP, CEP 13565-905, Brazil
| | - Alexandra Acco
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil
| | - Janaina Menezes Zanoveli
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR, 81540-990, Brazil.
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de Souza CP, Gambeta E, Stern CAJ, Zanoveli JM. Posttraumatic stress disorder-type behaviors in streptozotocin-induced diabetic rats can be prevented by prolonged treatment with vitamin E. Behav Brain Res 2018; 359:749-754. [PMID: 30219262 DOI: 10.1016/j.bbr.2018.09.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/04/2018] [Accepted: 09/12/2018] [Indexed: 01/05/2023]
Abstract
Anxiety and stress disorders, such as posttraumatic stress disorder (PTSD) have been described as debilitating comorbidities of diabetes. In the present study, we aimed to investigate anxiety-like behavior and the extinction and generalization of aversive memories in fear conditioning using a streptozotocin-induced model of diabetes (DBT). Moreover, considering that DBT animals present increased oxidative stress in brain areas related to anxiety and memory, we aimed to evaluate the effect of prolonged treatment with antioxidant vitamin E on behavioral parameters of anxiety and fear memory and on the diabetic condition. It was observed that DBT animals showed a deficiency in extinguishing the aversive memory in a fear conditioning test, along with a generalization of the fear memory. They also present a more pronounced anxiety-like behavior in the elevated plus maze test. VIT E treatment (300 mg/kg, p.o.) was not able to reduce hyperglycemia; however, it was able to block the anxiogenic-like behavior, also improving the deficit in the extinction of the aversive memory as well as blocking the generalization of such memory in a different context. Taken together, our data suggest that DBT animals are prone to extinction deficits and generalization of fear memories, behaviors which are observed in models of PTSD. Lastly, prolonged VIT E supplementation may be effective in the treatment of anxiety, extinction deficit and generalization of fear memories induced by the diabetic condition.
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Affiliation(s)
- Camila Pasquini de Souza
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Eder Gambeta
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil
| | | | - Janaína Menezes Zanoveli
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil.
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Patel SS, Ray RS, Sharma A, Mehta V, Katyal A, Udayabanu M. Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice. Metab Brain Dis 2018; 33:1281-1292. [PMID: 29704081 DOI: 10.1007/s11011-018-0243-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 04/17/2018] [Indexed: 01/17/2023]
Abstract
The present study was aimed to investigate the effect of Urtica dioica Linn. (UD) extract against chronic diabetes mediated anxiogenic and depressive like behavior in mice. Streptozotocin (STZ) (50 mg/kg, i.p.) for 5 consecutive days was used to induce diabetes followed by treatment with UD leaves extract (50 mg/kg, p.o.) and rosiglitazone (ROSI) (5 mg/kg, p.o.) for 8 weeks. STZ induced chronic diabetes significantly induced anxiety and depressive like behavior in mice. Chronic diabetes significantly downregulated BDNF (p < 0.001), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.05) and autophagy7 (p < 0.001), while upregulated iNOS (p < 0.05) mRNA expression in the hippocampus as compared to control mice. In addition, chronic diabetes significantly increased the expression of TNF-α in CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of hippocampus as compared to control mice. Chronic diabetes mediated neuronal damage in the CA2, CA3 and DG regions of hippocampus. Chronic administration of UD leaves extract significantly reversed diabetes mediated anxiogenic and depressive like behavior in mice. Further, UD treatment significantly upregulated BDNF (p < 0.01), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.01), autophagy5 (p < 0.01) and autophagy7 (p < 0.001), while downregulated iNOS (p < 0.05) mRNA expression in the hippocampus of diabetic mice. Concomitantly, UD administration significantly decreased the expression of TNF-α in hippocampal CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of diabetic mice. Diabetes mediated neuronal damage and DNA fragmentation in the hippocampus was substantially attenuated following UD treatment. UD leaves extract might prove to be effective for diabetes mediated anxiety and depressive like behavior.
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Affiliation(s)
- Sita Sharan Patel
- Department of Pharmacy, Jaypee University of Information Technology, Waknaghat, Himachal Pradesh, 173234, India
| | - R S Ray
- Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, North Campus, Delhi, 110 007, India
| | - Arun Sharma
- Department of Pharmacy, Jaypee University of Information Technology, Waknaghat, Himachal Pradesh, 173234, India
| | - Vineet Mehta
- Department of Pharmacy, Jaypee University of Information Technology, Waknaghat, Himachal Pradesh, 173234, India
| | - Anju Katyal
- Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, North Campus, Delhi, 110 007, India
| | - Malairaman Udayabanu
- Department of Pharmacy, Jaypee University of Information Technology, Waknaghat, Himachal Pradesh, 173234, India.
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Pechlivanova D, Petrov K, Grozdanov P, Nenchovska Z, Tchekalarova J, Stoynev A. Intracerebroventricular infusion of angiotensin AT2 receptor agonist novokinin aggravates some diabetes-mellitus-induced alterations in Wistar rats. Can J Physiol Pharmacol 2018; 96:471-478. [PMID: 29028440 DOI: 10.1139/cjpp-2017-0428] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Cumulative data suggest the significant role of the renin-angiotensin system in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of peptide AT2 agonist novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1DM) in Wistar rats. Food and water consumption, body mass, urine excretion (metabolic cages), motor activity (open-field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test), and plasma levels of glucose and corticosterone (ELISA) were assessed 2 weeks after the T1DM induction. Novokinin increased water and food consumption, as well as urine output, and reduced mass gain in the control rats. Diabetic rats demonstrated hyperalgesia, increased level of plasma corticosterone, decreased motor and exploratory activity, and impaired spatial memory. Novokinin infusion increased water intake, diuresis, and mortality rate, decreased food intake, exacerbated diabetes-induced hyperalgesia, and provoked anxiety-like behavior but improved spatial memory in diabetic rats. These initial data suggest that angiotensin AT2 receptors participate in the pathogenesis of T1DM-induced complications in the function of the nervous system.
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MESH Headings
- Animals
- Behavior, Animal/drug effects
- Corticosterone/metabolism
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/physiopathology
- Drinking/drug effects
- Exploratory Behavior/drug effects
- Infusions, Intraventricular
- Male
- Memory, Short-Term/drug effects
- Nociception/drug effects
- Oligopeptides/administration & dosage
- Oligopeptides/pharmacology
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 2/agonists
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Affiliation(s)
- D Pechlivanova
- a Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
| | - K Petrov
- b Department of Pathophysiology, Medical University-Sofia, 1 Georgi Sofiiski Str., 1431 Sofia, Bulgaria
| | - P Grozdanov
- c Institute of Microbiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
| | - Z Nenchovska
- a Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
| | - J Tchekalarova
- a Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
| | - A Stoynev
- b Department of Pathophysiology, Medical University-Sofia, 1 Georgi Sofiiski Str., 1431 Sofia, Bulgaria
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A serotonergic deficit in the dorsal periaqueductal gray matter may underpin enhanced panic-like behavior in diabetic rats. Behav Pharmacol 2018; 28:558-564. [PMID: 28799955 DOI: 10.1097/fbp.0000000000000332] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
It is known that diabetic (DBT) animals present dysregulation on the serotonergic system in several brain areas associated with anxiety-like responses. The aim of this study was to investigate the involvement of 5-HT1A receptors on dorsal periaqueductal gray (dPAG) in the behavioral response related to panic disorder in type-1 DBT animals. For this, the escape response by electric stimulation (ES) of dPAG in DBT and normoglycemic (NGL) animals was assessed. Both NGL and DBT animals were exposed to an open-field test (OFT) 28 days after DBT confirmation. The current threshold to induce escape behavior in DBT animals was reduced compared with NGL animals. No impairment in locomotor activity was observed when DBT animals were compared with NGL animals. An intra-dPAG injection of the 5-HT1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the [INCREMENT] threshold in both DBT and NGL, suggesting a panicolytic-like effect. DBT animals presented a more pronounced panicolytic-like response compared with NGL as a higher [INCREMENT] threshold was observed after 8-OH-DPAT treatment, which could be a consequence of the increased expression of the 5-HT1A receptor in the dPAG from DBT animals. Our results are in line with the proposal that a deficiency in serotonergic modulation of the dPAG is involved in triggering the panic attack and the 5-HT1A receptors might be essential for the panicolytic-like response.
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25
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Selakovic D, Joksimovic J, Zaletel I, Puskas N, Matovic M, Rosic G. The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin-positive interneurons. PLoS One 2017; 12:e0189595. [PMID: 29232412 PMCID: PMC5726625 DOI: 10.1371/journal.pone.0189595] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 11/28/2017] [Indexed: 11/18/2022] Open
Abstract
The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.
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Affiliation(s)
- Dragica Selakovic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Jovana Joksimovic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ivan Zaletel
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nela Puskas
- Institute of Histology and Embryology “Aleksandar Đ. Kostić”, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milovan Matovic
- Deparment of Nuclear Medicine, Faculty of Medical Sciences University of Kragujevac, Clinical Centre "Kragujevac", Kragujevac, Serbia
| | - Gvozden Rosic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- * E-mail:
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Ding S, Zhuge W, Wang X, Yang J, Lin Y, Wang C, Hu J, Zhuge Q. DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy. Front Cell Neurosci 2017; 11:258. [PMID: 28932186 PMCID: PMC5592740 DOI: 10.3389/fncel.2017.00258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 08/09/2017] [Indexed: 11/13/2022] Open
Abstract
Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.
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Affiliation(s)
- Saidan Ding
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Weishan Zhuge
- Gastrointestinal Surgery, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Xuebao Wang
- Analytical and Testing Center, Wenzhou Medical UniversityWenzhou, China
| | - Jianjing Yang
- Neurosurgery Department, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Yuanshao Lin
- Neurology Department, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Chengde Wang
- Neurosurgery Department, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Jiangnan Hu
- Neurosurgery Department, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Qichuan Zhuge
- Neurosurgery Department, First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
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Zegarra-Valdivia JA. Insulin-like growth factor type 1 and its relation with neuropsychiatric disorders. Medwave 2017; 17:e7031. [DOI: 10.5867/medwave.2017.07.7031] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 08/06/2017] [Indexed: 11/27/2022] Open
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28
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Siba IP, Bortolanza M, Frazão Vital MAB, Andreatini R, da Cunha JM, Del Bel EA, Zanoveli JM. Fish oil prevents rodent anxious states comorbid with diabetes: A putative involvement of nitric oxide modulation. Behav Brain Res 2017; 326:173-186. [DOI: 10.1016/j.bbr.2017.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 03/02/2017] [Accepted: 03/04/2017] [Indexed: 01/17/2023]
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Uysal N, Agilkaya S, Sisman AR, Camsari UM, Gencoglu C, Dayi A, Aksu I, Baykara B, Cingoz S, Kiray M. Exercise increases leptin levels correlated with IGF-1 in hippocampus and prefrontal cortex of adolescent male and female rats. J Chem Neuroanat 2017; 81:27-33. [DOI: 10.1016/j.jchemneu.2017.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 01/19/2017] [Accepted: 02/02/2017] [Indexed: 02/07/2023]
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30
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Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model. Prog Neuropsychopharmacol Biol Psychiatry 2016; 71:45-56. [PMID: 27328428 DOI: 10.1016/j.pnpbp.2016.06.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/31/2016] [Accepted: 06/16/2016] [Indexed: 01/22/2023]
Abstract
Anxiety frequently appears in patients with diabetic neuropathic pain, a highly prevalent clinical condition. However, the neurobiological mechanisms of this comorbidity are poorly known. Anxiogenic phenotype has been associated with alterations of the noradrenergic locus coeruleus (LC) after peripheral nerve entrapment. We have examined the sensorial (pain) and affective (anxiety) behaviors, and the LC activity in streptozotocin (STZ)-induced diabetic rats. A comparative study with the chronic constriction injury (CCI) model of sciatic nerve was also carried out. Diabetic nociceptive hypersensitivity was observed to appear gradually, reaching their maximum at fourth week. In contrast, CCI displayed a sharp decrease in their sensorial threshold at seventh day. In both models, anxiety-like phenotype was evident after four weeks but not earlier, coincident with the LC alterations. Indeed, STZ animals showed reduced LC firing activity, tyrosine hydroxylase, pCREB and noradrenaline transporter levels, contrary to observed in CCI animals. However, in both models, enhanced LC alpha2-adrenoceptor sensitivity was presented at this time point. This study demonstrated that diabetes induced anxiety-like behavior comorbid with LC impairment at long-term. However, the nociceptive sensitivity time-course, as well as the LC functions, showed distinct features compared to the CCI model, indicating that specific neuroplastic mechanisms are at play in every model.
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Kim S, Park S, Kim B, Kwon J. Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease. Sci Rep 2016; 6:27849. [PMID: 27279075 PMCID: PMC4899790 DOI: 10.1038/srep27849] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 05/25/2016] [Indexed: 12/20/2022] Open
Abstract
Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway's IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD.
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Affiliation(s)
- Sokho Kim
- Department of Laboratory Animal Medicine, Chonbuk National University, 79 Gobongro, Iksan, 54596, Republic of Korea
| | - Surim Park
- Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan, 54596, Republic of Korea
| | - Bumseok Kim
- Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan, 54596, Republic of Korea
| | - Jungkee Kwon
- Department of Laboratory Animal Medicine, Chonbuk National University, 79 Gobongro, Iksan, 54596, Republic of Korea
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Gambeta E, de Souza CP, de Morais H, Zanoveli JM. Reestablishment of the hyperglycemia to the normal levels seems not to be essential to the anxiolytic-like effect induced by insulin. Metab Brain Dis 2016; 31:563-71. [PMID: 26608284 DOI: 10.1007/s11011-015-9770-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 11/17/2015] [Indexed: 01/29/2023]
Abstract
Diabetes is a chronic metabolic disease accompanied by several comorbidities, including neuropsychiatric conditions. Since the hyperglycemia appears to be the primary factor involved in diabetic conditions, we examined the effect of insulin treatment in diabetic rats on behavioral responses related to anxiety and aversive memory extinction. For this, normoglycemic (NGL) or streptozotocin-diabetic (DBT) rats were submitted to the elevated T maze (ETM) and the contextual conditioned fear (CCF) tests. Therefore, animals were subjected to the prolonged treatment with insulin (6 IU/day, s.c.) to investigate the effect of the treatment on distinct behaviors. When anxiety-like responses such as the inhibitory avoidance (IA) on the ETM and the time of freezing in the first session of the CCF test were evaluated, our data showed a more pronounced anxiogenic-like behavior in DBT animals when compared to NGL ones. In addition, an increased freezing time was observed in DBT animals exposed to the CCF test (sessions 2 and 3) when compared to the NGL group, suggestive of an impairment in the extinction of aversive memory. Insulin treatment induced an anxiolytic-like effect when IA and freezing time (session 1) was evaluated, but did not alter the impaired extinction of aversive memory (sessions 2 and 3). To better understand the involvement of a rigorous control of glycaemia, we also investigated the effect of a lower dose of insulin (3 IU/day, s.c.), unable to reestablish the hyperglycemia to the normal levels, on the same behavioral parameters. Our data show that independent of the dose of insulin, the same effects were observed when animals were evaluated in the ETM and CCF tests. However, only the highest dose of insulin was able to reduce the hyperglycemia to the normal levels. To conclude, our data suggest that a severe glycemic control by insulin treatment seems to be important, but not essential in improving diabetes-induced anxiety.
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Affiliation(s)
- Eder Gambeta
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Avenida Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil
| | - Camila Pasquini de Souza
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Avenida Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil
| | - Helen de Morais
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Avenida Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil
| | - Janaina Menezes Zanoveli
- Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Avenida Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil.
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Maiese K. Erythropoietin and mTOR: A "One-Two Punch" for Aging-Related Disorders Accompanied by Enhanced Life Expectancy. Curr Neurovasc Res 2016; 13:329-340. [PMID: 27488211 PMCID: PMC5079807 DOI: 10.2174/1567202613666160729164900] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 07/12/2016] [Accepted: 07/14/2016] [Indexed: 12/16/2022]
Abstract
Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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Abstract
Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Gupta D, Thangaraj D, Radhakrishnan M. A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system. Behav Brain Res 2015; 297:41-50. [PMID: 26454237 DOI: 10.1016/j.bbr.2015.10.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 10/01/2015] [Accepted: 10/03/2015] [Indexed: 11/16/2022]
Abstract
Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.
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Affiliation(s)
- Deepali Gupta
- Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India.
| | - Devadoss Thangaraj
- KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh 520001, India
| | - Mahesh Radhakrishnan
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India
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Ying CJ, Zhang F, Zhou XY, Hu XT, Chen J, Wen XR, Sun Y, Zheng KY, Tang RX, Song YJ. Anti-inflammatory Effect of Astaxanthin on the Sickness Behavior Induced by Diabetes Mellitus. Cell Mol Neurobiol 2015; 35:1027-37. [PMID: 25971983 PMCID: PMC11486272 DOI: 10.1007/s10571-015-0197-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 04/14/2015] [Indexed: 12/17/2022]
Abstract
Chronic inflammation appears to play a critical role in sickness behavior caused by diabetes mellitus. Astaxanthin has been used in treating diabetes mellitus and diabetic complications because of its neuroprotective and anti-inflammatory actions. However, whether astaxanthin can improve sickness behavior induced by diabetes and its potential mechanisms are still unknown. The aim of this study was to investigate the effects of astaxanthin on diabetes-elicited abnormal behavior in mice and its corresponding mechanisms. An experimental diabetic model was induced by streptozotocin (150 mg/kg) and astaxanthin (25 mg/kg/day) was provided orally for 10 weeks. Body weight and water consumption were measured, and the sickness behavior was evaluated by the open field test (OFT) and closed field test (CFT). The expression of glial fibrillary acidic protein (GFAP) was measured, and the frontal cortical cleaved caspase-3 positive cells, interleukin-6 (IL-6), and interleukin-1β (IL-1β) expression levels were also investigated. Furthermore, cystathionine β-synthase (CBS) in the frontal cortex was detected to determine whether the protective effect of astaxanthin on sickness behavior in diabetic mice is closely related to CBS. As expected, we observed that astaxanthin improved general symptoms and significantly increase horizontal distance and the number of crossings in the OFT and CFT. Furthermore, data showed that astaxanthin could decrease GFAP-positive cells in the brain and down-regulate the cleaved caspase-3, IL-6, and IL-1β, and up-regulate CBS in the frontal cortex. These results suggest that astaxanthin provides neuroprotection against diabetes-induced sickness behavior through inhibiting inflammation, and the protective effects may involve CBS expression in the brain.
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Affiliation(s)
- Chang-jiang Ying
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Fang Zhang
- Laboratory of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Xiao-yan Zhou
- Laboratory of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Xiao-tong Hu
- Laboratory of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Jing Chen
- Laboratory of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Xiang-ru Wen
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Ying Sun
- Department of Neurology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Kui-yang Zheng
- Department of Pathogen Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Ren-xian Tang
- Laboratory of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China.
- Department of Pathogen Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China.
| | - Yuan-jian Song
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China.
- Department of Genetics, Research Center for Neurobiology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China.
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New Insights for Oxidative Stress and Diabetes Mellitus. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:875961. [PMID: 26064426 PMCID: PMC4443788 DOI: 10.1155/2015/875961] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 04/15/2015] [Indexed: 12/12/2022]
Abstract
The release of reactive oxygen species (ROS) and the generation of oxidative stress are considered critical factors for the pathogenesis of diabetes mellitus (DM), a disorder that is growing in prevalence and results in significant economic loss. New therapeutic directions that address the detrimental effects of oxidative stress may be especially warranted to develop effective care for the millions of individuals that currently suffer from DM. The mechanistic target of rapamycin (mTOR), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), and Wnt1 inducible signaling pathway protein 1 (WISP1) are especially justified to be considered treatment targets for DM since these pathways can address the complex relationship between stem cells, trophic factors, impaired glucose tolerance, programmed cell death pathways of apoptosis and autophagy, tissue remodeling, cellular energy homeostasis, and vascular biology that greatly impact the biology and disease progression of DM. The translation and development of these pathways into viable therapies will require detailed understanding of their proliferative nature to maximize clinical efficacy and limit adverse effects that have the potential to lead to unintended consequences.
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Hu P, Thinschmidt JS, Caballero S, Adamson S, Cole L, Chan-Ling T, Grant MB. Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. Am J Physiol Endocrinol Metab 2015; 308:E688-98. [PMID: 25714673 PMCID: PMC4398829 DOI: 10.1152/ajpendo.00504.2014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 02/13/2015] [Indexed: 02/02/2023]
Abstract
Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12- and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P<0.05) and reduced neuronal expression of IGFBP-3 (-32%, P<0.05) and IGF-I (-15%, P<0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P<0.01), and IDO⁺ cell density rose by (62%, P<0.05). CD39 expression dropped by 30% (P<0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P<0.05). Our results suggest that increased IDO and early loss of CD39⁺ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.
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Affiliation(s)
- Ping Hu
- Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia
| | - Jeffrey S Thinschmidt
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
| | - Sergio Caballero
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
| | - Samuel Adamson
- Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia
| | - Louise Cole
- Advanced Microscopy Facility, Bosch Institute, School of Medical Sciences, The University of Sydney, Camperdown, New South Wales, Australia; and
| | - Tailoi Chan-Ling
- Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia
| | - Maria B Grant
- Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University, Indianapolis, Indiana
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Maiese K. Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen Res 2015; 10:518-28. [PMID: 26170801 PMCID: PMC4424733 DOI: 10.4103/1673-5374.155427] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2015] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus affects almost 350 million individuals throughout the globe resulting in significant morbidity and mortality. Of further concern is the growing population of individuals that remain undiagnosed but are susceptible to the detrimental outcomes of this disorder. Diabetes mellitus leads to multiple complications in the central and peripheral nervous systems that include cognitive impairment, retinal disease, neuropsychiatric disease, cerebral ischemia, and peripheral nerve degeneration. Although multiple strategies are being considered, novel targeting of trophic factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1, and stem cell tissue regeneration are considered to be exciting prospects to overcome the cellular mechanisms that lead to neuronal injury in diabetes mellitus involving oxidative stress, apoptosis, and autophagy. Pathways that involve insulin-like growth factor-1, fibroblast growth factor, epidermal growth factor, and erythropoietin can govern glucose homeostasis and are intimately tied to Wnt signaling that involves Wnt1 and Wnt1 inducible signaling pathway protein 1 (CCN4) to foster control over stem cell proliferation, wound repair, cognitive decline, β-cell proliferation, vascular regeneration, and programmed cell death. Ultimately, cellular metabolism through Wnt signaling is driven by primary metabolic pathways of the mechanistic target of rapamycin and AMP activated protein kinase. These pathways offer precise biological control of cellular metabolism, but are exquisitely sensitive to the different components of Wnt signaling. As a result, unexpected clinical outcomes can ensue and therefore demand careful translation of the mechanisms that govern neural repair and regeneration in diabetes mellitus.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101, USA
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Maiese K. mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus. World J Diabetes 2015; 6:217-224. [PMID: 25789103 PMCID: PMC4360415 DOI: 10.4239/wjd.v6.i2.217] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 12/10/2014] [Accepted: 01/19/2015] [Indexed: 02/05/2023] Open
Abstract
The World Health Organization estimates that diabetes mellitus (DM) will become the seventh leading cause of death during the next two decades. DM affects approximately 350 million individuals worldwide and additional millions that remain undiagnosed are estimated to suffer from the complications of DM. Although the complications of DM can be seen throughout the body, the nervous, cardiac, and vascular systems can be significantly affected and lead to disorders that include cognitive loss, stroke, atherosclerosis, cardiac failure, and endothelial stem cell impairment. At the cellular level, oxidative stress is a significant determinant of cell fate during DM and leads to endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, and autophagy. Multiple strategies are being developed to combat the complications of DM, but it is the mechanistic target of rapamycin (mTOR) that is gaining interest in drug development circles especially for protective therapies that involve cytokines and growth factors such as erythropoietin. The pathways of mTOR linked to mTOR complex 1, mTOR complex 2, AMP activated protein kinase, and the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) complex can ultimately influence neuronal, cardiac, and vascular cell survival during oxidant stress in DM through a fine interplay between apoptosis and autophagy. Further understanding of these mTOR regulated pathways should foster novel strategies for the complications of DM that impact millions of individuals with death and disability.
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Maiese K. FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus. Curr Neurovasc Res 2015; 12:404-13. [PMID: 26256004 PMCID: PMC4567483 DOI: 10.2174/1567202612666150807112524] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 07/24/2015] [Accepted: 07/27/2015] [Indexed: 02/07/2023]
Abstract
Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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Maiese K. Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res 2015; 12:173-88. [PMID: 25742566 PMCID: PMC4380829 DOI: 10.2174/1567202612666150305110929] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 02/16/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022]
Abstract
According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.
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Affiliation(s)
- Kenneth Maiese
- MD, Cellular and Molecular Signaling, Newark, New Jersey 07101, USA.
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Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: possible implication of serotonergic system. Eur J Pharmacol 2014; 744:59-66. [PMID: 25284215 DOI: 10.1016/j.ejphar.2014.09.041] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 09/07/2014] [Accepted: 09/21/2014] [Indexed: 01/25/2023]
Abstract
Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg). After 8 weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1 mg/kg, p.o.)/fluoxetine (the positive control, 10 mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light-dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes-induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound.
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Uysal N, Kiray M, Sisman AR, Camsari UM, Gencoglu C, Baykara B, Cetinkaya C, Aksu I. Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotech Histochem 2014; 90:55-68. [PMID: 25203492 DOI: 10.3109/10520295.2014.946968] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Regular treadmill running during adolescence improves learning and memory in rats. During adolescence, the baseline level of stress is thought to be greater than during other periods of life. We investigated the effects of voluntary and involuntary exercise on the prefrontal cortex and hippocampus, vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) levels, and spatial learning, memory and anxiety in adolescent male and female rats. The voluntary exercise group was given free access to a running wheel for 6 weeks. The involuntary exercise group was forced to run on a treadmill for 30 min at 8 m/min 5 days/week for 6 weeks. Improved learning was demonstrated in both exercise groups compared to controls. Neuron density in the CA1 region of the hippocampus, dentate gyrus and prefrontal cortex were increased. Hippocampal VEGF and BDNF levels were increased in both exercise groups compared to controls. In females, anxiety and corticosterone levels were decreased; BDNF and VEGF levels were higher in the voluntary exercise group than in the involuntary exercise group. The adolescent hippocampus is affected favorably by regular exercise. Although no difference was found in anxiety levels as a result of involuntary exercise in males, females showed increased anxiety levels, and decreased VEGF and BDNF levels in the prefrontal cortex after involuntary exercise.
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Affiliation(s)
- N Uysal
- Department of Physiology, Dokuz Eylul University , Balcova, Izmir , Turkey
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46
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Gupta D, Radhakrishnan M, Kurhe Y. Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice. Metab Brain Dis 2014; 29:737-46. [PMID: 24763911 DOI: 10.1007/s11011-014-9540-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 03/27/2014] [Indexed: 02/06/2023]
Abstract
Clinical and preclinical data suggest that diabetes is often associated with anxiety. Insulin, a peptide hormone has been reported to have key functions in the brain and in alleviating several psychological impairments, occur as a consequence of diabetes. However, its effects in diabetes-induced anxiety are scanty. The present study examined whether; insulin can reverse the anxiety-like behavior in streptozotocin (STZ)-induced diabetes in mice. After 8-weeks of diabetes induced by STZ (200 mg/kg, intraperitoneally (i.p.)), mice were given insulin (1-2 IU/kg/day, i.p.)/ diazepam (1 mg/kg/day, i.p.)/ vehicle for 14 days and evaluated for behavioral effects in three validated models of anxiety viz. elevated plus maze (EPM), light-dark (L/D) and hole board (HB) tests. STZ-induced diabetic mice elicited significant behavioral effects which include, decreased percentage open arm entries and time in EPM, reduced latency and time spent in light chamber in L/D, decreased number of head dips, squares crossed and rearings in HB tests respectively. Insulin treatment attenuated the behavioral effects evoked by STZ-induced diabetes in mice as indicated by increased open arms activity in EPM, decreased aversion in light chamber during L/D test and increased exploratory behavior in HB test. In conclusion, this study revealed that insulin can reverse anxiety-like behavior in STZ-induced diabetes in mice.
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Affiliation(s)
- Deepali Gupta
- Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan, 333031, India,
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47
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Potential novel biomarkers for diabetic testicular damage in streptozotocin-induced diabetic rats: nerve growth factor Beta and vascular endothelial growth factor. DISEASE MARKERS 2014; 2014:108106. [PMID: 24771956 PMCID: PMC3977428 DOI: 10.1155/2014/108106] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 01/17/2014] [Accepted: 01/17/2014] [Indexed: 12/19/2022]
Abstract
Background. It is well known that diabetes mellitus may cause testicular damage. Vascular endothelial growth factor (VEGF) and nerve growth factor beta (NGF-β) are important neurotrophic factors for male reproductive system. Objective. We aimed to investigate the correlation between testicular damage and testicular VEGF and NGF-β levels in diabetic rats. Methods. Diabetes was induced by streptozotocin (STZ, 45 mg/kg/i.p.) in adult rats. Five weeks later testicular tissue was removed; testicular VEGF and NGF-β levels were measured by ELISA. Testicular damage was detected by using hematoxylin and eosin staining and periodic acid-Schiff staining, and apoptosis was identified by terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL). Seminiferous tubular sperm formation was evaluated using Johnsen's score. Results. In diabetic rats, seminiferous tubule diameter was found to be decreased; basement membrane was found to be thickened in seminiferous tubules and degenerated germ cells. Additionally, TUNEL-positive cells were increased in number of VEGF+ cells and levels of VEGF and NGF-β were decreased in diabetic testes. Correlation between VEGF and NGF-β levels was strong. Conclusion. These results suggest that the decrease of VEGF and NGF-β levels is associated with the increase of the apoptosis and testicular damage in diabetic rats. Testis VEGF and NGF-β levels could be potential novel biomarkers for diabetes induced testicular damage.
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Kiray M, Sisman AR, Camsari UM, Evren M, Dayi A, Baykara B, Aksu I, Ates M, Uysal N. Effects of carbon dioxide exposure on early brain development in rats. Biotech Histochem 2014; 89:371-83. [DOI: 10.3109/10520295.2013.872298] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Fiedorowicz A, Prokopiuk S, Zendzian-Piotrowska M, Chabowski A, Car H. Sphingolipid profiles are altered in prefrontal cortex of rats under acute hyperglycemia. Neuroscience 2013; 256:282-91. [PMID: 24161280 DOI: 10.1016/j.neuroscience.2013.10.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 09/12/2013] [Accepted: 10/10/2013] [Indexed: 12/14/2022]
Abstract
Diabetes type 1 is a common autoimmune disease manifesting by insulin deficiency and hyperglycemia, which can lead to dementia-like brain dysfunctions. The factors triggering the pathological processes in hyperglycemic brain remain unknown. We reported in this study that brain areas with different susceptibility to diabetes (prefrontal cortex (PFC), hippocampus, striatum and cerebellum) revealed differential alterations in ceramide (Cer) and sphingomyelin (SM) profiles in rats with streptozotocin-induced hyperglycemia. Employing gas-liquid chromatography, we found that level of total Cer increased significantly only in the PFC of diabetic animals, which also exhibited a broad spectrum of sphingolipid (SLs) changes, such as elevations of Cer-C16:0, -C18:0, -C20:0, -C22:0, -C18:1, -C24:1 and SM-C16:0 and -C18:1. In opposite, only minor changes were noted in other examined structures. In addition, de novo synthesis pathway could play a role in generation of Cer containing monounsaturated fatty acids in PFC during hyperglycemia. In turn, simultaneous accumulation of Cers and their SM counterparts may suggest that overproduced Cers are converted to SMs to avoid excessive Cer-mediated cytotoxicity. We conclude that broad changes in SLs compositions in PFC induced by hyperglycemia may provoke membrane rearrangements in some cell populations, which can disturb cellular signaling and cause tissue damage.
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Affiliation(s)
- A Fiedorowicz
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - S Prokopiuk
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - M Zendzian-Piotrowska
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland
| | - A Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland
| | - H Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland.
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Uysal N, Kiray M, Sisman AR, Baykara B, Aksu I, Dayi A, Gencoglu C, Evren M, Buyuk E, Cetin F, Acikgoz O. Effects of exercise and poor indoor air quality on learning, memory and blood IGF-1 in adolescent mice. Biotech Histochem 2013; 89:126-35. [DOI: 10.3109/10520295.2013.825318] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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