|
1
|
Bashir S, Faheem M, Alamoudi MK, Alnami A, Almehmadi KA, Khan AW, Almutairy B. Pharmacological and Computational Investigations of Isosteviol 16-oxime for Attenuating Streptozotocin-induced Diabetic Neuroinflammation utilizing rat as Animal Model. Int Immunopharmacol 2025; 153:114506. [PMID: 40147261 DOI: 10.1016/j.intimp.2025.114506] [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: 05/07/2024] [Revised: 03/12/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025]
Abstract
Diabetic neuropathy (DN) is microvascular issues caused by diabetes mellitus (DM) that damages peripheral nerve system. DN-induced pain progression and persistence occur due to many risk factors, including as increased TNF-α, NF-κB, and COX-2 levels. It was investigated whether Isosteviol 16-oxime (IO) could protect against DM-induced neuropathic pain. For this purpose streptozotocin-induced diabetic rat model was employed. After four weeks of streptozotocin injection, IO was given till the sixth week. On days 28, 31, 35, 38, and 42, behavioral assessments were done before and after Streptozotocin administration. After six weeks of streptozotocin treatment, rats were sacrificed, and spinal cord and sciatic nerve samples were taken for molecular analysis. The interaction kinetics and binding affinities of IO with TNF-α, NF-κB, and COX-2 targets were studied using computational methods. IO intervention significantly (P < 0.001) reduced mechanical allodynia and thermal hyperalgesia. The treatment of IO led to increased GSH, GST, and CAT concentrations in the spinal cord and sciatic nerve, while reducing LPO levels (P < 0.001). IHC and Nissl staining showed that IO successfully reduced DN-induced pathological changes. IO also down regulated the expression of inflammatory mediators TNF-α, NF-κB, and COX-2, suggesting its potential as a neuroprotective drug. In comparison to pregabalin, IO demonstrated enhanced antinociceptive properties and diminished hyperalgesic effects. Consequently, IO exhibits a more pronounced reduction in pain perception and inflammation. Our investigation found that IO may protect against DM-induced neuroinflammation by suppressing cytokines and increasing antioxidant levels. More research is needed to determine the exact mechanism of IO in neuroprotection and pain reduction.
Collapse
Affiliation(s)
- Saud Bashir
- Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Muhammad Faheem
- Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
| | - Mariam K Alamoudi
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Aisha Alnami
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Khulood A Almehmadi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Abdul Waheed Khan
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
| |
Collapse
|
|
2
|
Chong ZZ, Souayah N. Neuroinflammation in diabetic peripheral neuropathy and therapeutic implications. Rev Neurosci 2025:revneuro-2025-0031. [PMID: 40228523 DOI: 10.1515/revneuro-2025-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 03/28/2025] [Indexed: 04/16/2025]
Abstract
Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes mellitus, which is a common cause of disability in individuals with diabetes mellitus. Multiple mechanisms may be involved in the development of DPN. Neuroinflammation is a critical factor contributing to nerve damage during diabetes. Inflammation can induce the development of diabetes mellitus, and long-term hyperglycemia also causes increased oxidative stress and promotes the release of inflammatory cytokines. After reading through the literature, the association of inflammation with the induction of diabetes and DPN was discussed in the review. Inflammation induces nerve damage and nerve conduction impairment. The neuropathic pain in diabetes-induced DPN is also closely associated with the inflammatory response. Given the important roles of inflammation in diabetes-induced DPN, explicit elucidation of neuroinflammation during diabetes mellitus and DPN should hold the potential for developing novel therapeutic strategies for DPN. Experimental studies and limited clinical trials support the value of anti-inflammatory reagents in treating DPN, and the positive outcomes of these investigations warrant further clinical trials.
Collapse
Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, New Jersey Medical School, Rutgers University, 185 S Orange, Newark, NJ 07103, USA
| | - Nizar Souayah
- Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA
| |
Collapse
|
|
3
|
Moqbel Redhwan MA, M G H, Samaddar S, Bafail D, Hard SAAA, Guha S, Dhavale A. siRNA targeting PARP-1 alleviates diabetic peripheral neuropathy in a streptozotocin-induced rat model. J Drug Target 2025; 33:424-435. [PMID: 39565138 DOI: 10.1080/1061186x.2024.2431316] [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: 08/17/2024] [Revised: 10/31/2024] [Accepted: 11/13/2024] [Indexed: 11/21/2024]
Abstract
Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, affecting nearly 50% of diabetic patients and leading to chronic pain, numbness and progressive sensory and motor function loss. This study investigates the potential of siRNA-mediated silencing of poly(ADP-ribose) polymerase 1 (PARP1) to alleviate DPN in a rat model. PARP1 overactivation, driven by hyperglycaemia-induced oxidative stress, exacerbates neuronal damage in DPN. Using chitosan nanoparticles (ChNPs) to deliver PARP1-targeting siRNA intrathecally in diabetic rats induced with streptozotocin (STZ) 55 mg/kg intraperitoneally, we conducted behavioural and physiological assessments, including Sciatic Functional Index (SFI), motor nerve conduction velocity (MNCV), grip strength and pain sensitivity tests, alongside qRT-PCR analyses, to evaluate therapeutic outcomes. Our findings indicate statistically significant improvements, with siRNA ChNPs-mediated PARP1 silencing alleviating neuropathic symptoms in DPN rats (p < .001 for SFI and MNCV improvements). Biochemical analyses revealed reductions in oxidative stress markers, such as MDA, and increased antioxidant levels, including GSH, CAT and SOD (p < .001). Pro-inflammatory cytokines and apoptotic markers, including NF-κB, IL6, IL1β, TNFa, TGF-β, CAS3, CAS9, BAK and BAX, also showed significant reductions (p < .01), confirming the neuroprotective effects of PARP1 inhibition. These results highlight the potential of siRNA-based therapies targeting PARP1 as a promising therapeutic approach for DPN, paving the way for future research with clinical applications.
Collapse
Affiliation(s)
- Moqbel Ali Moqbel Redhwan
- Department of Pharmacology, KLE College of Pharmacy, Bengaluru, India
- Basic Science Research Center (Off-Campus), KLE College of Pharmacy, Bengaluru, India
| | - Hariprasad M G
- Department of Pharmacology, KLE College of Pharmacy, Bengaluru, India
- Basic Science Research Center (Off-Campus), KLE College of Pharmacy, Bengaluru, India
| | - Suman Samaddar
- BGS GIMS Research Institute, BGS Global Institute of Medical Sciences, Bengaluru, India
| | - Duaa Bafail
- Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sumaia Abdulbari Ahmed Ali Hard
- Basic Science Research Center (Off-Campus), KLE College of Pharmacy, Bengaluru, India
- Department of Pharmaceutics, KLE College of Pharmacy, Bengaluru, India
| | - Sourav Guha
- Department of Pharmacology, KLE College of Pharmacy, Bengaluru, India
- Basic Science Research Center (Off-Campus), KLE College of Pharmacy, Bengaluru, India
| | - Apurwa Dhavale
- Department of Pharmacology, KLE College of Pharmacy, Bengaluru, India
- Basic Science Research Center (Off-Campus), KLE College of Pharmacy, Bengaluru, India
| |
Collapse
|
|
4
|
Chong ZZ, Menkes DL, Souayah N. Targeting neuroinflammation in distal symmetrical polyneuropathy in diabetes. Drug Discov Today 2024; 29:104087. [PMID: 38969091 DOI: 10.1016/j.drudis.2024.104087] [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: 09/19/2023] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Diabetic distal symmetric polyneuropathy is the most common type of peripheral neuropathy complication of diabetes mellitus. Neuroinflammation is emerging as an important contributor to diabetes-induced neuropathy. Long-term hyperglycemia results in increased production of advanced glycation end products (AGEs). AGEs interact with their receptors to activate intracellular signaling, leading to the release of various inflammatory cytokines. Increased release of inflammatory cytokines is associated with diabetes, diabetic neuropathy, and neuropathic pain. Thus, anti-inflammatory intervention is a potential therapy for diabetic distal symmetric polyneuropathy. Further characterization of inflammatory mechanisms might identify novel therapeutic targets to mitigate diabetic neuropathy.
Collapse
Affiliation(s)
- Zhao Zhong Chong
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
| | - Daniel L Menkes
- Department of Neurology, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
| | - Nizar Souayah
- Department of Neurology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, USA.
| |
Collapse
|
|
5
|
Ratan Y, Rajput A, Pareek A, Pareek A, Kaur R, Sonia S, Kumar R, Singh G. Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy. Biomedicines 2024; 12:1390. [PMID: 39061964 PMCID: PMC11273858 DOI: 10.3390/biomedicines12071390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Diabetic neuropathy (DN) is a neurodegenerative disorder that is primarily characterized by distal sensory loss, reduced mobility, and foot ulcers that may potentially lead to amputation. The multifaceted etiology of DN is linked to a range of inflammatory, vascular, metabolic, and other neurodegenerative factors. Chronic inflammation, endothelial dysfunction, and oxidative stress are the three basic biological changes that contribute to the development of DN. Although our understanding of the intricacies of DN has advanced significantly over the past decade, the distinctive mechanisms underlying the condition are still poorly understood, which may be the reason behind the lack of an effective treatment and cure for DN. The present study delivers a comprehensive understanding and highlights the potential role of the several pathways and molecular mechanisms underlying the etiopathogenesis of DN. Moreover, Schwann cells and satellite glial cells, as integral factors in the pathogenesis of DN, have been enlightened. This work will motivate allied research disciplines to gain a better understanding and analysis of the current state of the biomolecular mechanisms behind the pathogenesis of DN, which will be essential to effectively address every facet of DN, from prevention to treatment.
Collapse
Affiliation(s)
- Yashumati Ratan
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aishwarya Rajput
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Ashutosh Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aaushi Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Ranjeet Kaur
- Adesh Institute of Dental Sciences and Research, Bathinda 151101, Punjab, India;
| | - Sonia Sonia
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India;
| | - Rahul Kumar
- Baba Ragav Das Government Medical College, Gorakhpur 273013, Uttar Pradesh, India;
| | - Gurjit Singh
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA
| |
Collapse
|
|
6
|
Amiri B, Yazdani Tabrizi M, Naziri M, Moradi F, Arzaghi M, Archin I, Behaein F, Bagheri Pour A, Ghannadikhosh P, Imanparvar S, Akhtari Kohneshahri A, Sanaye Abbasi A, Zerangian N, Alijanzadeh D, Ghayyem H, Azizinezhad A, Ahmadpour Youshanlui M, Poudineh M. Neuroprotective effects of flavonoids: endoplasmic reticulum as the target. Front Neurosci 2024; 18:1348151. [PMID: 38957188 PMCID: PMC11218733 DOI: 10.3389/fnins.2024.1348151] [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: 12/01/2023] [Accepted: 03/28/2024] [Indexed: 07/04/2024] Open
Abstract
The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell's intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.
Collapse
Affiliation(s)
- Bita Amiri
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Yazdani Tabrizi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdyieh Naziri
- Student Research Committee, School of Health, Iran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Moradi
- Student Research Committee, School of Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Arzaghi
- Department of Physical Education and Sports Science-Nutrition, Branch Islamic Azad University, Tehran, Iran
| | - Iman Archin
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Parna Ghannadikhosh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Imanparvar
- School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ata Akhtari Kohneshahri
- Student Research Committee, Faculty of Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Ali Sanaye Abbasi
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nasibeh Zerangian
- PhD Student in Health Education and Health Promotion, Department of Health Education and Health Promotion, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dorsa Alijanzadeh
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hani Ghayyem
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Azizinezhad
- Universal Scientific Education and Research Network (USERN), Tabriz, Iran
| | | | - Mohadeseh Poudineh
- Student Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran
| |
Collapse
|
|
7
|
Samora M, Huo Y, Stanhope KL, Havel PJ, Kaufman MP, Harrison ML, Stone AJ. Cyclooxygenase products contribute to the exaggerated exercise pressor reflex evoked by static muscle contraction in male UCD-type 2 diabetes mellitus rats. J Appl Physiol (1985) 2024; 136:1226-1237. [PMID: 38545661 PMCID: PMC11368523 DOI: 10.1152/japplphysiol.00879.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/25/2024] [Accepted: 03/25/2024] [Indexed: 05/15/2024] Open
Abstract
Cyclooxygenase (COX) products of arachidonic acid metabolism, specifically prostaglandins, play a role in evoking and transmitting the exercise pressor reflex in health and disease. Individuals with type 2 diabetes mellitus (T2DM) have an exaggerated exercise pressor reflex; however, the mechanisms for this exaggerated reflex are not fully understood. We aimed to determine the role played by COX products in the exaggerated exercise pressor reflex in T2DM rats. The exercise pressor reflex was evoked by static muscle contraction in unanesthetized, decerebrate, male, adult University of California Davis (UCD)-T2DM (n = 8) and healthy Sprague-Dawley (n = 8) rats. Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) during muscle contraction were compared before and after intra-arterial injection of indomethacin (1 mg/kg) into the contracting hindlimb. Data are presented as means ± SD. Inhibition of COX activity attenuated the exaggerated peak MAP (Before: Δ32 ± 13 mmHg and After: Δ18 ± 8 mmHg; P = 0.004) and blood pressor index (BPi) (Before: Δ683 ± 324 mmHg·s and After: Δ361 ± 222 mmHg·s; P = 0.006), but not HR (Before: Δ23 ± 8 beats/min and After Δ19 ± 10 beats/min; P = 0.452) responses to muscle contraction in T2DM rats. In healthy rats, COX activity inhibition did not affect MAP, HR, or BPi responses to muscle contraction. Inhibition of COX activity significantly reduced local production of prostaglandin E2 in T2DM and healthy rats. We conclude that peripheral inhibition of COX activity attenuates the pressor response to muscle contraction in T2DM rats, suggesting that COX products partially contribute to the exaggerated exercise pressor reflex in those with T2DM.NEW & NOTEWORTHY We compared the pressor and cardioaccelerator responses to static muscle contraction before and after inhibition of cyclooxygenase (COX) activity within the contracting hindlimb in decerebrate, unanesthetized type 2 diabetic mellitus (T2DM) and healthy rats. The pressor responses to muscle contraction were attenuated after peripheral inhibition of COX activity in T2DM but not in healthy rats. We concluded that COX products partially contribute to the exaggerated pressor reflex in those with T2DM.
Collapse
Affiliation(s)
- Milena Samora
- Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas, United States
| | - Yu Huo
- Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas, United States
| | - Kimber L Stanhope
- Department of Molecular Biosciences, School of Veterinary Medicine and Department of Nutrition, University of California Davis, Davis, California, United States
| | - Peter J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine and Department of Nutrition, University of California Davis, Davis, California, United States
| | - Marc P Kaufman
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States
| | - Michelle L Harrison
- Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas, United States
| | - Audrey J Stone
- Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas, United States
| |
Collapse
|
|
8
|
Cheng Y, Chen Y, Li K, Liu S, Pang C, Gao L, Xie J, Wenjing LV, Yu H, Deng B. How inflammation dictates diabetic peripheral neuropathy: An enlightening review. CNS Neurosci Ther 2024; 30:e14477. [PMID: 37795833 PMCID: PMC11017439 DOI: 10.1111/cns.14477] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/28/2023] [Accepted: 09/08/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) constitutes a debilitating complication associated with diabetes. Although, the past decade has seen rapid developments in understanding the complex etiology of DPN, there are no approved therapies that can halt the development of DPN, or target the damaged nerve. Therefore, clarifying the pathogenesis of DPN and finding effective treatment are the crucial issues for the clinical management of DPN. AIMS This review is aiming to summary the current knowledge on the pathogenesis of DPN, especially the mechanism and application of inflammatory response. METHODS We systematically summarized the latest studies on the pathogenesis and therapeutic strategies of diabetic neuropathy in PubMed. RESULTS In this seminal review, the underappreciated role of immune activation in the progression of DPN is scrutinized. Novel insights into the inflammatory regulatory mechanisms of DPN have been unearthed, illuminating potential therapeutic strategies of notable clinical significance. Additionally, a nuanced examination of DPN's complex etiology, including aberrations in glycemic control and insulin signaling pathways, is presented. Crucially, an emphasis has been placed on translating these novel understandings into tangible clinical interventions to ameliorate patient outcomes. CONCLUSIONS This review is distinguished by synthesizing cutting-edge mechanisms linking inflammation to DPN and identifying innovative, inflammation-targeted therapeutic approaches.
Collapse
Affiliation(s)
- Yifan Cheng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's HospitalAffiliated People's Hospital, Hangzhou Medical CollegeHangzhouChina
| | - Yinuo Chen
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Kezheng Li
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Shuwei Liu
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Chunyang Pang
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Lingfei Gao
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Jiali Xie
- Department of Neurology, Shanghai East HospitalTongji UniversityShanghaiP.R. China
| | - L. V. Wenjing
- Department of GeriatricsThe Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina
| | - Huan Yu
- Department of PediatricsSecond Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Binbin Deng
- Department of NeurologyFirst Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
- First School of Clinical MedicineWenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| |
Collapse
|
|
9
|
Aziz N, Dash B, Wal P, Kumari P, Joshi P, Wal A. New Horizons in Diabetic Neuropathies: An Updated Review on their Pathology, Diagnosis, Mechanism, Screening Techniques, Pharmacological, and Future Approaches. Curr Diabetes Rev 2024; 20:e201023222416. [PMID: 37867268 DOI: 10.2174/0115733998242299231011181615] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/16/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need. METHODS The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause. RESULT Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored. CONCLUSION This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications.
Collapse
Affiliation(s)
- Namra Aziz
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Biswajit Dash
- Department of Pharmaceutical Technology, School of Medical Sciences, ADAMAS University, Kolkata 700 126, West Bengal, India
| | - Pranay Wal
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Prachi Kumari
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| | - Poonam Joshi
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun 248007, Uttarakhand, India
| | - Ankita Wal
- Pranveer Singh Institute of Technology (Pharmacy), Bhauti, Kanpur 209305, UP, India
| |
Collapse
|
|
10
|
Hashim M, Badruddeen, Akhtar J, Khan MI, Ahmad M, Islam A, Ahmad A. Diabetic Neuropathy: An Overview of Molecular Pathways and Protective Mechanisms of Phytobioactives. Endocr Metab Immune Disord Drug Targets 2024; 24:758-776. [PMID: 37867264 DOI: 10.2174/0118715303266444231008143430] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/31/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
Diabetic neuropathy (DN) is a common and debilitating complication of diabetes mellitus that affects the peripheral nerves and causes pain, numbness, and impaired function. The pathogenesis of DN involves multiple molecular mechanisms, such as oxidative stress, inflammation, and pathways of advanced glycation end products, polyol, hexosamine, and protein kinase C. Phytochemicals are natural compounds derived from plants that have various biological activities and therapeutic potential. Flavonoids, terpenes, alkaloids, stilbenes, and tannins are some of the phytochemicals that have been identified as having protective potential for diabetic neuropathy. These compounds can modulate various cellular pathways involved in the development and progression of neuropathy, including reducing oxidative stress and inflammation and promoting nerve growth and repair. In this review, the current evidence on the effects of phytochemicals on DN by focusing on five major classes, flavonoids, terpenes, alkaloids, stilbenes, and tannins, are summarized. This compilation also discusses the possible molecular targets of numerous pathways of DN that these phytochemicals modulate. These phytochemicals may offer a promising alternative or complementary approach to conventional drugs for DN management by modulating multiple pathological pathways and restoring nerve function.
Collapse
Affiliation(s)
- Mohd Hashim
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Badruddeen
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Juber Akhtar
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | | | - Mohammad Ahmad
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| | - Asad Ahmad
- Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
11
|
Josifovska S, Panov S, Hadzi-Petrushev N, Mitrokhin V, Kamkin A, Stojchevski R, Avtanski D, Mladenov M. Positive Tetrahydrocurcumin-Associated Brain-Related Metabolomic Implications. Molecules 2023; 28:3734. [PMID: 37175144 PMCID: PMC10179939 DOI: 10.3390/molecules28093734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/22/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Tetrahydrocurcumin (THC) is a metabolite of curcumin (CUR). It shares many of CUR's beneficial biological activities in addition to being more water-soluble, chemically stable, and bioavailable compared to CUR. However, its mechanisms of action have not been fully elucidated. This paper addresses the preventive role of THC on various brain dysfunctions as well as its effects on brain redox processes, traumatic brain injury, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease in various animal or cell culture models. In addition to its strong antioxidant properties, the effects of THC on the reduction of amyloid β aggregates are also well documented. The therapeutic potential of THC to treat patterns of mitochondrial brain dysmorphic dysfunction is also addressed and thoroughly reviewed, as is evidence from experimental studies about the mechanism of mitochondrial failure during cerebral ischemia/reperfusion injury. THC treatment also results in a dose-dependent decrease in ERK-mediated phosphorylation of GRASP65, which prevents further compartmentalization of the Golgi apparatus. The PI3K/AKT signaling pathway is possibly the most involved mechanism in the anti-apoptotic effect of THC. Overall, studies in various animal models of different brain disorders suggest that THC can be used as a dietary supplement to protect against traumatic brain injury and even improve brain function in Alzheimer's and Parkinson's diseases. We suggest further preclinical studies be conducted to demonstrate the brain-protective, anti-amyloid, and anti-Parkinson effects of THC. Application of the methods used in the currently reviewed studies would be useful and should help define doses and methods of THC administration in different disease conditions.
Collapse
Affiliation(s)
- Slavica Josifovska
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
| | - Sasho Panov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
| | - Vadim Mitrokhin
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| | - Andre Kamkin
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| | - Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| |
Collapse
|
|
12
|
Elgarawany GE, Badawy AD, Hazzaa SM. Co Q10 improves vascular reactivity in male diabetic rats by enhancing insulin sensitivity and antioxidant effect. Arch Physiol Biochem 2023; 129:108-115. [PMID: 32718232 DOI: 10.1080/13813455.2020.1798465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oxidative stress is the main player in the development of diabetic vascular complications. Co-Q10 is a natural antioxidant present in the body and in many foods. This study was designed to evaluate the effect of Co-Q10 administration to improve vascular complications and increase insulin sensitivity in diabetic rats. Fifty male rats were divided into five groups: control, diabetic untreated, diabetic insulin-treated, diabetic Co-Q10-treated, and diabetic combined-treated groups. After 8 weeks, blood pressure and vascular reactivity to NE and ACh, fasting glucose, insulin, C-peptide, MDA, TAC, HbA1c, and the HOMA-IR were measured. Diabetes increased fasting glucose, HbA1c, HOMA-IR, MDA, blood pressure, and decreased TAC and vascular reactivity. Ttreatment with insulin or Co-Q10 improved glycemic parameters and increasing antioxidant levels compared to diabetic group. Combined Co-Q10 with insulin was found to increase insulin sensitivity and decrease its resistance, which helps to decrease insulin doses in diabetic patients and reduce its side effects.
Collapse
Affiliation(s)
- Ghada E Elgarawany
- Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebeen El Kom, Egypt
- Department of Biomedical Science, Faculty of Medicine, Gulf Medical University, UAE
| | - Ahmed Desoky Badawy
- Department of Medical Physiology, Faculty of Medicine, 6 October University, 6 October City, Egypt
| | - Suzan M Hazzaa
- Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebeen El Kom, Egypt
| |
Collapse
|
|
13
|
Drug repurposing – A search for novel therapy for the treatment of diabetic neuropathy. Biomed Pharmacother 2022; 156:113846. [DOI: 10.1016/j.biopha.2022.113846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/27/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
|
|
14
|
Faheem M, Khan AU, Shah FA, Li S. Investigation of Natural Compounds for Therapeutic Potential in Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain. Front Pharmacol 2022; 13:1019033. [PMID: 36278164 PMCID: PMC9581174 DOI: 10.3389/fphar.2022.1019033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/02/2022] [Indexed: 11/15/2022] Open
Abstract
Diabetic neuropathy (DN) is a serious microvascular complication of diabetes mellitus (DM) that impacts the nervous system. Several risk factors are involved in the progression and maintenance of DN-associated pain, such as higher expression of various inflammatory mediators, e.g., tumor necrotic factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclo-oxygenase-2 (COX-2). The present research explores the neuroprotective potential of natural isolates, including berbamine, bergapten, and carveol, on the DM-induced neuroinflammation and neurodegeneration that cause neuropathic pain. The study utilized computerized techniques, including computational analysis (a docking assay and a molecular dynamic simulation) before moving to in vivo protocols. Diabetic neuropathy was induced by intraperitonial injection (IP) of streptozotocin (65 mg/kg), and the animal subjects (rats) were kept for 4 weeks for the development of DN. Once diabetic neuropathy was confirmed, the subjects were treated with berbamine, bergapten, and carveol until the sixth week (i.e., 2 weeks of treatment). At the sixth week, the rats were sacrificed, and the sciatic nerve and spinal cord of each was collected for further molecular investigation. Docking and a molecular dynamic simulation (MDS) delivered the information that the natural compounds (berbamine, bergapten, and carveol) were interacting with the selected target protein (i.e., mitogen-activated protein kinase). After IP, it was found that berbamine, bergapten, and carveol had ameliorated mechanical allodynia and thermal hyperalgesia by the 28th day of the study (2 weeks after treatment) without affecting blood glucose levels. Berbamine, bergapten, and carveol markedly elevated the levels of glutathione (GSH) and glutathione s-transferase (GST), in both the sciatic nerve and spinal cord, and also reduced lipid peroxidase (LPO) and nitric oxide (NO). The abovementioned natural isolates reduced pathologic alterations provoked through DN, a finding confirmed through histopathological assays (hematoxylin and eosin staining and immuno-histochemical analysis). Treatment down regulated higher expressions of the inflammatory mediatorcyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB), as confirmed by ELISA and polymerase chain reaction (PCR). The outcomes of berbamine, bergapten, and carveol are compared with those of pregabalin as a positive control group. Compared to pregabalin, treatment with the aforementioned three natural compounds improved nociception and reduced hyperalgesic effects, and consequently reduced pain perception and inflammation. Our results suggest the mechanism for the neuro-protective impact of berbamine, bergapten, and carveol might possibly be arbitrated via COX-2, TNF-α, and NF-κB, and regulated by mitogen-activated protein kinase, ultimately ameliorating STZ-provoked, DM-induced neuroinflammation and neurodegeneration, and associated neuropathic pain.
Collapse
Affiliation(s)
- Muhammad Faheem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Arif-ullah Khan
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
- *Correspondence: Arif-ullah Khan, ; Shupeng Li,
| | - Fawad Ali Shah
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China
- *Correspondence: Arif-ullah Khan, ; Shupeng Li,
| |
Collapse
|
|
15
|
Luna R, Talanki Manjunatha R, Bollu B, Jhaveri S, Avanthika C, Reddy N, Saha T, Gandhi F. A Comprehensive Review of Neuronal Changes in Diabetics. Cureus 2021; 13:e19142. [PMID: 34868777 PMCID: PMC8628358 DOI: 10.7759/cureus.19142] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 12/11/2022] Open
Abstract
There has been an exponential rise in diabetes mellitus (DM) cases on a global scale. Diabetes affects almost every system of the body, and the nervous system is no exception. Although the brain is dependent on glucose, providing it with the energy required for optimal functionality, glucose also plays a key role in the regulation of oxidative stress, cell death, among others, which furthermore contribute to the pathophysiology of neurological disorders. The variety of biochemical processes engaged in this process is only matched by the multitude of clinical consequences resulting from it. The wide-ranging effects on the central and peripheral nervous system include, but are not limited to axonopathies, neurodegenerative diseases, neurovascular diseases, and general cognitive impairment. All language search was conducted on MEDLINE, COCHRANE, EMBASE, and GOOGLE SCHOLAR till September 2021. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "CNS," "Diabetic Neuropathy," and "Insulin." We explored the literature on diabetic neuropathy, covering its epidemiology, pathophysiology with the respective molecular pathways, clinical consequences with a special focus on the central nervous system and finally, measures to prevent and treat neuronal changes. Diabetes is slowly becoming an epidemic, rapidly increasing the clinical burden on account of its wide-ranging complications. This review focuses on the neuronal changes occurring in diabetes such as the impact of hyperglycemia on brain function and structure, its association with various neurological disorders, and a few diabetes-induced peripheral neuropathic changes. It is an attempt to summarize the relevant literature about neuronal consequences of DM as treatment options available today are mostly focused on achieving better glycemic control; further research on novel treatment options to prevent or delay the progression of neuronal changes is still needed.
Collapse
Affiliation(s)
- Rudy Luna
- Neurofisiología, Instituto Nacional de Neurologia y Neurocirugia, CDMX, MEX
| | | | | | | | - Chaithanya Avanthika
- Medicine and Surgery; Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Nikhil Reddy
- Internal Medicine, Kamineni Academy of Medical Science and Research Centre, Hyderabad, IND
| | - Tias Saha
- Internal Medicine, Diabetic Association Medical College, Faridpur, BGD
| | - Fenil Gandhi
- Medicine, Shree Krishna Hospital, Anand, IND
- Research Project Associate, Memorial Sloan Kettering Cancer Center, New York, USA
| |
Collapse
|
|
16
|
Cheng X, Zhao L, Ke T, Wang X, Cao L, Liu S, He J, Rong W. Celecoxib ameliorates diabetic neuropathy by decreasing apoptosis and oxidative stress in dorsal root ganglion neurons via the miR-155/COX-2 axis. Exp Ther Med 2021; 22:825. [PMID: 34149871 PMCID: PMC8200812 DOI: 10.3892/etm.2021.10257] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Celecoxib (CXB) is the only clinical cyclooxygenase-2 (COX-2) inhibitor. Oral administration of CXB in experimental diabetic mice effectively relieved the symptoms of diabetic neuropathy (DN); however, the molecular mechanism remains unclear. The present study aimed to investigate the potential molecular mechanisms of CXB in the treatment of DN. An in vitro cellular model of DN was produced by stimulating dorsal root ganglion (DRG) neurons with high glucose. Cell viability and apoptosis were assessed by Cell Counting Kit-8 assays and flow cytometry, respectively. Reactive oxygen species (ROS) kits, ELISA kits and western blotting were used to determine oxidative cellular damage. The expression level of microRNA (miR)-155 was analyzed by reverse transcription-quantitative PCR. The starBase database and dual-luciferase assays were performed to predict and determine the interaction between miR-155 and COX-2. Protein expression of neurotrophic factors, oxidative stress-related proteins and COX-2 were analyzed by western blotting. Incubation with high glucose led to a decrease in DRG neuron cell viability, facilitated apoptosis, downregulated NGF and BDNF expression, increased ROS and MDA generation and decreased SOD activity. Treatment with CXB significantly protected DRG neurons against high glucose-evoked damage. CXB promoted the expression of miR-155 and COX-2 was revealed to be a direct target of miR-155. Inhibition of COX-2 enhanced the protective effect of CXB on DRG neurons and that treatment with an miR-155 inhibitor partially rescued this effect. The present study demonstrated the involvement of the miR-155/COX-2 axis in the protective effect of CXB against high glucose-induced DN.
Collapse
Affiliation(s)
- Xiaoliang Cheng
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Ling Zhao
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Tingyu Ke
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Xi Wang
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Lijun Cao
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Shuyan Liu
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Jie He
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Wei Rong
- Department of Neurology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| |
Collapse
|
|
17
|
Alaaeddine RA, Elzahhar PA, AlZaim I, Abou-Kheir W, Belal ASF, El-Yazbi AF. The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs). Curr Med Chem 2021; 28:2260-2300. [PMID: 32867639 DOI: 10.2174/0929867327999200820173853] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 11/22/2022]
Abstract
Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.
Collapse
Affiliation(s)
- Rana A Alaaeddine
- Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon
| | - Perihan A Elzahhar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ibrahim AlZaim
- Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon
| | - Ahmed S F Belal
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ahmed F El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon
| |
Collapse
|
|
18
|
Adefegha SA, Dada FA, Oyeleye SI, Oboh G. Effects of berberine on cholinesterases and monoamine oxidase activities, and antioxidant status in the brain of streptozotocin (STZ)-induced diabetic rats. J Basic Clin Physiol Pharmacol 2021; 33:389-397. [PMID: 33725758 DOI: 10.1515/jbcpp-2020-0173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 01/23/2021] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Several studies had been conducted to examine the link between diabetes and diabetes encephalopathy. This study was conducted to examine the potency of berberine (BER) on the restoration of impaired neurochemicals in the brain of streptozotocin (STZ)-induced diabetic Wistar rats. METHODS Fifty-six (56) adult rats weighing between 200 and 230 g were randomly divided into seven groups (n=8) as follows; Group I is normal control; Groups II and III were normal rats treated with 50 and 100 mg/kg respectively; Group IV-VII were STZ-induced rats, but Groups V-VII were treated with acarbose (25 mg/kg), 50 and 100 mg/kg of BER, respectively. RESULTS The result of the study showed that untreated STZ-induced diabetic rats have increased acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO) activities, and malonylaldehyde (MDA) level, with concomitant decrease of superoxide dismutase (SOD), glutathione peroxidase (GPx) activities, and glutathione (GSH) level. However, daily treatment with 50 and 100 mg/kg BER and ACA significantly reversed these effects. CONCLUSIONS The findings of this study clearly indicated that BER possesses neuro-protective and antioxidative potentials and normalize neurochemical impairment distort by diabetes.
Collapse
Affiliation(s)
- Stephen A Adefegha
- Functional Foods and Nutraceuticals Research Laboratory, Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Felix A Dada
- Science Laboratory Technology Department (Biochemistry Unit), Ede, Osun State, Nigeria
| | - Sunday I Oyeleye
- Functional Foods and Nutraceuticals Research Laboratory, Biochemistry Department, Federal University of Technology, Akure, Nigeria
| | - Ganiyu Oboh
- Functional Foods and Nutraceuticals Research Laboratory, Biochemistry Department, Federal University of Technology, Akure, Nigeria
| |
Collapse
|
|
19
|
Abstract
Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.
Collapse
|
|
20
|
|
|
21
|
Gautam M, Ramanathan M. Ameliorative potential of flavonoids of Aegle marmelos in vincristine-induced neuropathic pain and associated excitotoxicity. Nutr Neurosci 2019; 24:296-306. [PMID: 31221045 DOI: 10.1080/1028415x.2019.1627768] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: The objective of the study is to elucidate the effect of Aegle marmelos bark hydroalcoholic extract (AMHE) and the role of its constituents marmelosin, umbelliferone, and Para-coumaric acid in attenuating neuropathic pain.Methodology: Peripheral neuropathy was induced by vincristine 100 μg/ml. AMHE was administered in three dose levels (100, 200 and 300 mg/kg) for 21 days. Mechanical hyperalgesia and allodynia were assessed by Randall Sellitto and electronic Von-Frey test, respectively. Functional loss and recovery of the nerve were assessed by sciatic functional index test. The nerve conduction velocity and formalin test were done to assess the peripheral and central response of the extract. Inflammatory mediators in both sciatic nerve and brain and neurotransmitters glutamate and aspartate were measured to support the data.Results and discussion: The inflammatory mediators in both sciatic nerve and brain (TNF-α, IL-1β, and IL-6) were found to be attenuated with AMHE-treated group in comparison to the group treated only with vincristine, which indicates the extract has anti-inflammatory property. AMHE treated rats were found to be active in all the behavioural tests, suggesting its activity could be mediated through a central and peripheral mechanism to attenuate the pain response. The levels of excitatory neurotransmitters were found to be reduced with AMHE treatment.Conclusion: It could be concluded that AMHE is active in attenuating the neuropathic pain caused by vincristine. The peripheral action would have mediated through lowering the inflammatory mediators as well as the excitotoxicity caused due to peripheral neuropathy and neuroinflammation.
Collapse
Affiliation(s)
- Mrinmoy Gautam
- Department of Pharmacology, PSG College of Pharmacy, Coimbatore, India
| | | |
Collapse
|
|
22
|
Farias VX, Uchoa PN, Aquino CP, Britto LRG, Fonteles MC, Leal-Cardoso JH, Silva-Alves KS, Havt A, Prata MMG, Heimark DB, Nascimento NRF, Santos CF. Expression of myo-inositol cotransporters in the sciatic nerve and dorsal root ganglia in experimental diabetes. ACTA ACUST UNITED AC 2019; 52:e8589. [PMID: 31166385 PMCID: PMC6556969 DOI: 10.1590/1414-431x20198589] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 04/09/2019] [Indexed: 02/03/2023]
Abstract
The transport of myo-inositol is the main mechanism for the maintenance of its high intracellular levels. We aimed to measure the mRNA and protein levels of myo-inositol cotransporters in the sciatic nerve (SN) and dorsal root ganglia (DRG) during experimental diabetes. Streptozotocin-induced (STZ; 4, 8, and 12 weeks; 65 mg/kg; ip) diabetic rats (DB) and age-matched euglycemic (E) rats were used for the analysis of mRNA and protein levels of sodium myo-inositol cotransporters 1, 2 (SMIT1, SMIT2) or H+/myo-inositol cotransporter (HMIT). There was a significant reduction in the mRNA levels for SMIT1 in the SN and DRG (by 36.9 and 31.0%) in the 4-week DB (DB4) group compared to the E group. SMIT2 was not expressed in SN. The mRNA level for SMIT2 was up-regulated only in the DRG in the DB4 group. On the other hand, the protein level of SMIT1 decreased by 42.5, 41.3, and 44.8% in the SN after 4, 8, and 12 weeks of diabetes, respectively. In addition, there was a decrease of 64.3 and 58.0% of HMIT in membrane and cytosolic fractions, respectively, in the SN of the DB4 group. In the DRG, there was an increase of 230 and 86.3% for SMIT1 and HMIT, respectively, in the DB12 group. The levels of the main inositol transporters, SMIT1 and HMIT, were greatly reduced in the SN but not in the DRG. SMIT-1 was selectively reduced in the sciatic nerve during experimental STZ-induced diabetes.
Collapse
Affiliation(s)
- V X Farias
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - P N Uchoa
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - C P Aquino
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - L R G Britto
- Instituto de Ciências Biomédicas, Laboratório de Neurofisiologia, Universidade de São Paulo, SP, Brasil
| | - M C Fonteles
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - J H Leal-Cardoso
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - K S Silva-Alves
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - A Havt
- Instituto de Ciências Biomédicas, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - M M G Prata
- Instituto de Ciências Biomédicas, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - D B Heimark
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - N R F Nascimento
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| | - C F Santos
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, CE, Brasil
| |
Collapse
|
|
23
|
Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018; 107:306-328. [PMID: 30098549 DOI: 10.1016/j.biopha.2018.07.157] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/15/2018] [Accepted: 07/31/2018] [Indexed: 02/09/2023] Open
Abstract
Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.
Collapse
Affiliation(s)
- Biplab Giri
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India.
| | - Sananda Dey
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Tanaya Das
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Mrinmoy Sarkar
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India.
| |
Collapse
|
|
24
|
Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 175] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
|
|
25
|
Tsantoulas C, Laínez S, Wong S, Mehta I, Vilar B, McNaughton PA. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci Transl Med 2018; 9:eaam6072. [PMID: 28954930 DOI: 10.1126/scitranslmed.aam6072] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/22/2017] [Accepted: 09/06/2017] [Indexed: 01/12/2023]
Abstract
Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice. In addition, we found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. We propose that the increased intracellular cAMP drives diabetes-associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers. Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.
Collapse
Affiliation(s)
- Christoforos Tsantoulas
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK
| | - Sergio Laínez
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK
| | - Sara Wong
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK
| | - Ishita Mehta
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK
| | - Bruno Vilar
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK
| | - Peter A McNaughton
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
| |
Collapse
|
|
26
|
Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy. Anesthesiology 2018; 128:609-619. [DOI: 10.1097/aln.0000000000002035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Abstract
Background
Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes.
Methods
We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (14C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity.
Results
First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons.
Conclusions
We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.
Collapse
|
|
27
|
Bachewal P, Gundu C, Yerra VG, Kalvala AK, Areti A, Kumar A. Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy. Biofactors 2018; 44:109-122. [PMID: 29193444 DOI: 10.1002/biof.1397] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 10/06/2017] [Accepted: 10/10/2017] [Indexed: 12/20/2022]
Abstract
Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.
Collapse
Affiliation(s)
- Pragna Bachewal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Chayanika Gundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Veera Ganesh Yerra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Anil Kumar Kalvala
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Aparna Areti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| |
Collapse
|
|
28
|
Nasiry D, khalatbary AR, Ahmadvand H, Talebpour Amiri F, Akbari E. Protective effects of methanolic extract of Juglans regia L. leaf on streptozotocin-induced diabetic peripheral neuropathy in rats. Altern Ther Health Med 2017; 17:476. [PMID: 28969623 PMCID: PMC5625610 DOI: 10.1186/s12906-017-1983-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/22/2017] [Indexed: 12/20/2022]
Abstract
Background Oxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat. Methods The DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments. Results Degeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction. Conclusion Our results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties. Graphical abstract Protection against neuropathy![]()
Collapse
|
|
29
|
Yerra VG, Kalvala AK, Kumar A. Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy. J Nutr Biochem 2017; 47:41-52. [DOI: 10.1016/j.jnutbio.2017.05.001] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/20/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
|
|
30
|
Salimnejad R, Sazegar G, Saeedi Borujeni MJ, Mousavi SM, Salehi F, Ghorbani F. Protective effect of hydroalcoholic extract of Teucrium polium on diabetes-induced testicular damage and serum testosterone concentration. Int J Reprod Biomed 2017. [DOI: 10.29252/ijrm.15.4.195] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
|
|
31
|
Atif F, Prunty MC, Turan N, Stein DG, Yousuf S. Progesterone modulates diabetes/hyperglycemia-induced changes in the central nervous system and sciatic nerve. Neuroscience 2017; 350:1-12. [DOI: 10.1016/j.neuroscience.2017.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/01/2017] [Accepted: 03/03/2017] [Indexed: 12/21/2022]
|
|
32
|
Kandimalla R, Dash S, Kalita S, Choudhury B, Malampati S, Devi R, Ramanathan M, Talukdar NC, Kotoky J. Bioactive Fraction of Annona reticulata Bark (or) Ziziphus jujuba Root Bark along with Insulin Attenuates Painful Diabetic Neuropathy through Inhibiting NF-κB Inflammatory Cascade. Front Cell Neurosci 2017; 11:73. [PMID: 28381989 PMCID: PMC5361110 DOI: 10.3389/fncel.2017.00073] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 02/28/2017] [Indexed: 02/01/2023] Open
Abstract
The present study explains the neuroprotective ability of bioactive fractions of Annona reticulata bark (ARB) and Ziziphus jujuba root bark (ZJ) along with insulin against diabetic neuropathy. By using different solvents of increasing polarity ARB and ZJ were undergone for bioactive guided fractionation. The neuroprotective ability of the all the plant fractions were tested against H2O2 induced toxicity in SHSY5Y neuroblastoma cell lines and DRG neuronal cells. Among all the fractions tested, the methanol extract of ARB and ZJ (ARBME and ZJME) and its water fractions (ARBWF and ZJWF) exhibited significant neuroprotection against H2O2 induced toxicity in SHSY5Y cells and DRG neuronal cells. Further both the active fractions were tested against streptozotocin (55 mg/kg i.p.) induced diabetic neuropathy in male Wistar rats. Body weight changes, blood glucose levels and pain threshold through hot plate, tail immersion, cold plate and Randall-Sillitto methods were measured throughout the study at weekly interval. After completion of the drug treatment period, all the animals were sacrificed to measure the sciatic nerve lipid peroxidation, antioxidative enzyme levels (SOD, catalase, and GSH) and cytokine levels (IL-1β, IL-6, IL-10, TNF-α, iNOS, and NFκB) through ELISA and western blotting analysis. Results of this study explain that ARBME, ZJME, ARBWF, and ZJWF along with insulin potentially attenuate the thermal, mechanical hyperalgesia and cold allodynia in diabetic neuropathic rats, where insulin treatment alone failed to diminish the same. Reduction of sciatic nerve oxidative stress, NF-κB and iNOS mediated inflammatory cascade and normalization of abnormal cytokine release confirms the possible mechanism of action. The present study confirms the neuroprotective ability of ARB and ZJ against painful diabetic neuropathy through inhibiting oxidative stress and NF-κB inflammatory cascade.
Collapse
Affiliation(s)
- Raghuram Kandimalla
- Drug Discovery Laboratory, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Suvakanta Dash
- Girijananda Chowdhury Institute of Pharmaceutical Science Guwahati, India
| | - Sanjeeb Kalita
- Drug Discovery Laboratory, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Bhaswati Choudhury
- Drug Discovery Laboratory, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Sandeep Malampati
- School of Chinese Medicine, Hong Kong Baptist University Kowloon Tong, Hong Kong
| | - Rajlakshmi Devi
- Drug Discovery Laboratory, Institute of Advanced Study in Science and Technology Guwahati, India
| | | | - Narayan C Talukdar
- Drug Discovery Laboratory, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Jibon Kotoky
- Drug Discovery Laboratory, Institute of Advanced Study in Science and TechnologyGuwahati, India; National Institute of Pharmaceutical Education and ResearchGuwahati, India
| |
Collapse
|
|
33
|
HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain. Biochem J 2016; 473:2717-36. [DOI: 10.1042/bcj20160287] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 05/18/2016] [Indexed: 01/22/2023]
Abstract
Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.
Collapse
|
|
34
|
Gong SS, Li YX, Zhang MT, Du J, Ma PS, Yao WX, Zhou R, Niu Y, Sun T, Yu JQ. Neuroprotective Effect of Matrine in Mouse Model of Vincristine-Induced Neuropathic Pain. Neurochem Res 2016; 41:3147-3159. [PMID: 27561290 DOI: 10.1007/s11064-016-2040-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 07/17/2016] [Accepted: 08/19/2016] [Indexed: 12/18/2022]
Abstract
Chemotherapy drugs such as vincristine (VCR) can cause neuropathic pain, and there is still lack of ideal strategy to treat it. The current study was designed to investigate effect of matrine (MT) on VCR-induced neuropathic pain in animal model. VCR (75 μg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy model in mice. MT (15, 30 and 60 mg/kg, i.p.) and pregabalin (10 mg/kg, i.p.) were administered for 11 consecutive days. Various tests were performed to assess the degree of pain at different days (1, 6, 11, 16, and 21). Von Frey hair, hot plate, cold-plate and paw pressure tests were conducted to assess the degree of mechanical allodynia, thermal hyperalgesia, cold allodynia and mechanical hyperalgesia in the hind paw respectively. The electrophysiological and histopathological changes were also analyzed. Furthermore, tissue malondialdehyde (MDA), total antioxidant capacity (T-AOC),superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total calcium (TCA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) were measured to investigate possible involvement of MT in inflammation and oxidative stress. Administration of MT attenuated the VCR-induced behavioral alterations as well as electrophysiological and histopathological changes in a dose dependent manner. Further, MT also attenuated the VCR-induced oxidative stress (MDA, T-AOC, GSH-Px, SOD and TCA) and inflammation (MPO, TNF-α, IL-6 and IL-10). Taken together, MT ameliorated VCR-induced painful neuropathy, which might be attributed to neuroprotective effects by subsequent reduction in oxidative stress and anti-inflammatory actions.
Collapse
Affiliation(s)
- Shuai-Shuai Gong
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Yu-Xiang Li
- College of Nursing, Ningxia Medical University, Yinchuan, 750004, China
| | - Meng-Ting Zhang
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Juan Du
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Peng-Sheng Ma
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Wan-Xia Yao
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Ru Zhou
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China
| | - Yang Niu
- Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China
| | - Tao Sun
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, 750004, China
| | - Jian-Qiang Yu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Xingqing, Ningxia Hui Autonomous Region, Yinchuan, 750004, China. .,Ningxia Hui Medicine Modern Engineering Research Center and Collaborative Innovation Center, Ningxia Medical University, Yinchuan, 750004, China.
| |
Collapse
|
|
35
|
Sung SK, Woo JS, Kim YH, Son DW, Lee SW, Song GS. Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells. J Korean Neurosurg Soc 2016; 59:259-68. [PMID: 27226858 PMCID: PMC4877549 DOI: 10.3340/jkns.2016.59.3.259] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/11/2015] [Accepted: 01/30/2016] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity. METHODS HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity. RESULTS AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells. CONCLUSION Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.
Collapse
Affiliation(s)
- Soon Ki Sung
- Department of Neurosurgery, Pusan National University School of Medicine, Busan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Busan, Korea
| | - Jae Suk Woo
- Department of Physiology, Pusan National University School of Medicine, Busan, Korea
| | - Young Ha Kim
- Department of Neurosurgery, Pusan National University School of Medicine, Busan, Korea
| | - Dong Wuk Son
- Department of Neurosurgery, Pusan National University School of Medicine, Busan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Busan, Korea
| | - Sang Weon Lee
- Department of Neurosurgery, Pusan National University School of Medicine, Busan, Korea
| | - Geun Sung Song
- Department of Neurosurgery, Pusan National University School of Medicine, Busan, Korea
| |
Collapse
|
|
36
|
Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation. Mol Neurobiol 2016; 54:2301-2312. [PMID: 26957299 DOI: 10.1007/s12035-016-9824-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/02/2016] [Indexed: 12/20/2022]
Abstract
Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague-Dawley rats (250-270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-κB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN.
Collapse
|
|
37
|
Greeshma N, Prasanth K, Balaji B. Tetrahydrocurcumin exerts protective effect on vincristine induced neuropathy: Behavioral, biochemical, neurophysiological and histological evidence. Chem Biol Interact 2015; 238:118-28. [DOI: 10.1016/j.cbi.2015.06.025] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 05/21/2015] [Accepted: 06/18/2015] [Indexed: 12/17/2022]
|
|
38
|
Babu A, Prasanth KG, Balaji B. Effect of curcumin in mice model of vincristine-induced neuropathy. PHARMACEUTICAL BIOLOGY 2015; 53:838-848. [PMID: 25429779 DOI: 10.3109/13880209.2014.943247] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. OBJECTIVE The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. MATERIALS AND METHODS Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. RESULTS Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p < 0.001) and allodynia (p < 0.001); mechanical hyperalgesia (p < 0.001); functional loss (p < 0.001); and in the delayed phase of formalin test (p < 0.001). Curcumin at 30 and 60 mg/kg exhibited significant changes (p < 0.001) in antioxidant levels and in total calcium levels in vincristine-injected mice. CONCLUSION Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.
Collapse
Affiliation(s)
- Anand Babu
- Department of Pharmacology, PSG College of Pharmacy , Coimbatore, Tamil Nadu , India
| | | | | |
Collapse
|
|
39
|
Downs CA, Faulkner MS. Toxic stress, inflammation and symptomatology of chronic complications in diabetes. World J Diabetes 2015; 6:554-565. [PMID: 25987953 PMCID: PMC4434076 DOI: 10.4239/wjd.v6.i4.554] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/30/2014] [Accepted: 02/12/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes affects at least 382 million people worldwide and the incidence is expected to reach 592 million by 2035. The incidence of diabetes in youth is skyrocketing as evidenced by a 21% increase in type 1 diabetes and a 30.5% increase in type 2 diabetes in the United States between 2001 and 2009. The effects of toxic stress, the culmination of biological and environmental interactions, on the development of diabetes complications is gaining attention. Stress impacts the hypothalamus-pituitary-adrenal axis and contributes to inflammation, a key biological contributor to the pathogenesis of diabetes and its associated complications. This review provides an overview of common diabetic complications such as neuropathy, cognitive decline, depression, nephropathy and cardiovascular disease. The review also provides a discussion of the role of inflammation and stress in the development and progression of chronic complications of diabetes, associated symptomatology and importance of early identification of symptoms of depression, fatigue, exercise intolerance and pain.
Collapse
|
|
40
|
Agrawal NK, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014; 5:697-710. [PMID: 25317247 PMCID: PMC4138593 DOI: 10.4239/wjd.v5.i5.697] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 04/24/2014] [Accepted: 05/29/2014] [Indexed: 02/05/2023] Open
Abstract
Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications.
Collapse
|
|
41
|
Abstract
Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end‐products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ‐specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long‐term hyperglycemia are critical for peripheral nerve damage, resulting in distal‐predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00070.x, 2010)
Collapse
Affiliation(s)
| | | | - Kazuhiro Sugimoto
- Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| |
Collapse
|
|
42
|
Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol 2014; 2014:674987. [PMID: 24883061 PMCID: PMC4021687 DOI: 10.1155/2014/674987] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 03/14/2014] [Indexed: 02/06/2023] Open
Abstract
In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50-60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy. Mitochondria induced ROS and other oxidants are responsible for altering the balance between oxidants and innate antioxidant defence of the body. Oxidative-nitrosative stress not only activates the major pathways namely, polyol pathway flux, advanced glycation end products formation, activation of protein kinase C, and overactivity of the hexosamine pathway, but also initiates and amplifies neuroinflammation. The cross talk between oxidative stress and inflammation is due to the activation of NF- κ B and AP-1 and inhibition of Nrf2, peroxynitrite mediate endothelial dysfunction, altered NO levels, and macrophage migration. These all culminate in the production of proinflammatory cytokines which are responsible for nerve tissue damage and debilitating neuropathies. This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy.
Collapse
Affiliation(s)
- Reddemma Sandireddy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Bala Nagar, Hyderabad 500037, India
| | - Veera Ganesh Yerra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Bala Nagar, Hyderabad 500037, India
| | - Aparna Areti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Bala Nagar, Hyderabad 500037, India
| | - Prashanth Komirishetty
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Bala Nagar, Hyderabad 500037, India
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Bala Nagar, Hyderabad 500037, India
- *Ashutosh Kumar:
| |
Collapse
|
|
43
|
Stavniichuk R, Obrosov AA, Drel VR, Nadler JL, Obrosova IG, Yorek MA. 12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy. ACTA ACUST UNITED AC 2013; 3. [PMID: 24175152 DOI: 10.4236/jdm.2013.33015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Increased mitogen-activated protein kinase (MAPK) phosphorylation has been detected in peripheral nerve of human subjects and animal models with diabetes as well as high-glucose exposed human Schwann cells, and have been implicated in diabetic peripheral neuropathy. In our recent studies, leukocytetype 12/15-lipoxygenase inhibition or gene deficiency alleviated large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss in streptozotocin-diabetic mice. METHODS To address a mechanism we evaluated the potential for pharmacological 12/15-lipoxygenase inhibition to counteract excessive MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy. C57Bl6/J mice were made diabetic with streptozotocin and maintained with or without the 12/15-lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC). Human Schwann cells were cultured in 5.5 mM or 30 mM glucose with or without CDC. RESULTS 12(S) HETE concentrations (ELISA), as well as 12/15-lipoxygenase expression and p38 MAPK, ERK, and SAPK/JNK phosphorylation (all by Western blot analysis) were increased in the peripheral nerve and spinal cord of diabetic mice as well as in high glucose-exposed human Schwann cells. CDC counteracted diabetes-induced increase in 12(S)HETE concentrations (a measure of 12/15-lipoxygenase activity), but not 12/15-lipoxygenase overexpression, in sciatic nerve and spinal cord. The inhibitor blunted excessive p38 MAPK and ERK, but not SAPK/ JNK, phosphorylation in sciatic nerve and high glucose exposed human Schwann cells, but did not affect MAPK, ERK, and SAPK/JNK phosphorylation in spinal cord. CONCLUSION 12/15-lipoxygenase inhibition counteracts diabetes related MAPK phosphorylation in mouse and cell culture models of diabetic neuropathy and implies that 12/15-lipoxygenase inhibitors may be an effective treatment for diabetic peripheral neuropathy.
Collapse
Affiliation(s)
- Roman Stavniichuk
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, USA
| | | | | | | | | | | |
Collapse
|
|
44
|
Ranjithkumar R, Prathab Balaji S, Balaji B, Ramesh RV, Ramanathan M. Standardized Aqueous Tribulus terristris (nerunjil) extract attenuates hyperalgesia in experimentally induced diabetic neuropathic pain model: role of oxidative stress and inflammatory mediators. Phytother Res 2012; 27:1646-57. [PMID: 23280817 DOI: 10.1002/ptr.4915] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Revised: 11/17/2012] [Accepted: 11/27/2012] [Indexed: 12/31/2022]
Abstract
The present study aimed to evaluate standardized aqueous Tribulus terristris (nerunjil) extract on the pain threshold response in streptozotocin (STZ)-induced diabetic neuropathic pain model in rats. After a single injection of STZ (40 mg/kg; i.p.), Wistar male rats were tested by the thermal and chemical-induced pain models. Diabetic rats exhibited significant hyperalgesia, and these rats were left untreated for the first four weeks. Thereafter, treatment was initiated and continued up to week-8. All the rats except the vehicle-treated group received insulin 5 IU/kg/day to maintain plasma glucose levels. Treatment with nerunjil (100 and 300 mg/kg; p.o.) for 4 weeks significantly attenuated the nociception in behavioural models. Nerunjil also inhibited the tumour necrosis factor-α and interleukin-1 beta levels. The effect of nerunjil (300 mg/kg) is comparable to the standard drug Pregabalin (100 mg/kg). Nerunjil increased the superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and decreased the lipid peroxide levels in dose-dependent manner. Insulin alone-treated rats failed to attenuate hyperalgesic response. In comparison to insulin alone-treated rats, nerunjil exhibited significant increase in the pain threshold response. It could be concluded that in controlled diabetic states, nerunjil attenuated the neuropathic pain through modulation of oxidative stress and inflammatory cytokine release.
Collapse
|
|
45
|
Tahrani AA, Ali A, Raymond NT, Begum S, Dubb K, Mughal S, Jose B, Piya MK, Barnett AH, Stevens MJ. Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med 2012; 186:434-41. [PMID: 22723291 DOI: 10.1164/rccm.201112-2135oc] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. OBJECTIVES To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. METHODS A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. MEASUREMENTS AND MAIN RESULTS Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. CONCLUSIONS We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.
Collapse
Affiliation(s)
- Abd A Tahrani
- Centre of Endocrinology, Diabetes, and Metabolism, University of Birmingham, Birmingham, United Kingdom.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Sung JY, Park SB, Liu YT, Kwai N, Arnold R, Krishnan AV, Lin CSY. Progressive axonal dysfunction precedes development of neuropathy in type 2 diabetes. Diabetes 2012; 61:1592-8. [PMID: 22522615 PMCID: PMC3357264 DOI: 10.2337/db11-1509] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA(1c) levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0-1 [n = 35]), grade 1 (TNS 2-8 [n = 42]), and grade 2/3 (TNS 9-24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA(1c) level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.
Collapse
Affiliation(s)
- Jia-Ying Sung
- Department of Neurology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Susanna B. Park
- Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Randwick, Sydney, New South Wales, Australia
| | - Ya-Ting Liu
- Department of Neurology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Natalie Kwai
- School of Medical Sciences and Translational Neuroscience Facility, Faculty of Medicine, University of New South Wales, Randwick, Sydney, New South Wales, Australia
| | - Ria Arnold
- School of Medical Sciences and Translational Neuroscience Facility, Faculty of Medicine, University of New South Wales, Randwick, Sydney, New South Wales, Australia
| | - Arun V. Krishnan
- School of Medical Sciences and Translational Neuroscience Facility, Faculty of Medicine, University of New South Wales, Randwick, Sydney, New South Wales, Australia
| | - Cindy S.-Y. Lin
- Department of Neurology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- School of Medical Sciences and Translational Neuroscience Facility, Faculty of Medicine, University of New South Wales, Randwick, Sydney, New South Wales, Australia
- Corresponding author: Cindy S.-Y. Lin,
| |
Collapse
|
|
47
|
Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization. Pain 2012; 153:553-561. [DOI: 10.1016/j.pain.2011.11.019] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 11/16/2011] [Accepted: 11/16/2011] [Indexed: 11/19/2022]
|
|
48
|
Takata H, Takeda Y, Zhu A, Cheng Y, Yoneda T, Demura M, Yagi K, Karashima S, Yamagishi M. Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats. Diabetes Obes Metab 2012; 14:155-162. [PMID: 21951301 DOI: 10.1111/j.1463-1326.2011.01499.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
AIMS Mineralocorticoid receptor (MR) blockade is an effective treatment for hypertension and diabetic nephropathy. There are no data on the effects of MR blockade on diabetic peripheral neuropathy (DPN). The aim of this study was to determine whether MRs are present in the peripheral nerves and to investigate the effectiveness of MR blockade on DPN in streptozotocin (STZ)-induced diabetic rats. METHODS Expression of MR protein and messenger RNA (mRNA) was examined in the peripheral nerves using Western blot analysis and RT-PCR. We next studied the effects of the selective MR antagonist eplerenone and the angiotensin II receptor blocker candesartan on motor and sensory nerve conduction velocity (NCV), morphometric changes and cyclooxygenase-2 (COX-2) gene and NF-κB protein expression in the peripheral nerves of STZ-induced diabetic rats. RESULTS Expression of MR protein and mRNA in peripheral nerves was equal to that in the kidney. Motor NCV was significantly improved by 8 weeks of treatment with either eplerenone (39.1 ± 1.2 m/s) or candesartan (46.4 ± 6.8 m/s) compared with control diabetic rats (33.7 ± 2.0 m/s) (p < 0.05). Sensory NCV was also improved by treatment with candesartan or eplerenone in diabetic rats. Eplerenone and candesartan caused significant improvement in mean myelin fibre area and mean myelin area compared with control diabetic rats (p < 0.05). COX-2 mRNA and NF-κB protein were significantly elevated in the peripheral nerves of diabetic rats compared with control rats, and treatment with eplerenone or candesartan reduced these changes in gene expression (p < 0.05). CONCLUSION MR blockade may have neuroprotective effects on DPN.
Collapse
Affiliation(s)
- H Takata
- Division of Endocrinology and Hypertension, Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Chauhan N, Taliyan R, Sharma PL. Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain. Naunyn Schmiedebergs Arch Pharmacol 2012; 385:527-38. [PMID: 22249337 DOI: 10.1007/s00210-011-0724-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Accepted: 12/28/2011] [Indexed: 02/07/2023]
Abstract
Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-α) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-α up-regulation activates nuclear factor κB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-α and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-α inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy.
Collapse
Affiliation(s)
- Neha Chauhan
- Department of Pharmacology, I.S.F College of Pharmacy, Moga, 142001, Punjab, India
| | | | | |
Collapse
|
|
50
|
Kumar A, Negi G, Sharma SS. JSH-23 targets nuclear factor-kappa B and reverses various deficits in experimental diabetic neuropathy: effect on neuroinflammation and antioxidant defence. Diabetes Obes Metab 2011; 13:750-8. [PMID: 21447040 DOI: 10.1111/j.1463-1326.2011.01402.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
AIM Nuclear factor-kappa B (NF-κB) being reported to play an important role in the pathogenesis of diabetic neuropathy is believed to be a central mechanism involved in the genesis and promulgation of inflammatory insult. Here we have targeted the nuclear translocation of NF-κB using JSH-23 to elucidate its role in diabetic neuropathy. METHODS JSH-23 (1 and 3 mg/kg) was administered for 2 weeks in diabetic rats, after 6 weeks of diabetes induction using streptozotocin (55 mg/kg) as diabetogenic agent. Functional (motor nerve conduction velocity and blood flow), behavioural (mechanical hyperalgesia), biochemical [malondialdehyde, glutathione, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels] and NF-κB translocation studies (western blot technique) were then undertaken. RESULTS JSH-23 treatment significantly reversed the nerve conduction and nerve blood flow deficits seen in diabetic animals. Reduction in mechanical pain threshold was also partially corrected by the treatment. Protein expression studies showed that nuclear translocation of p65/p50 subunit was inhibited by JSH-23 treatment in the sciatic nerve. The treatment also lowered the elevated IL-6, TNF-α, cyclo-oxygenase (COX-2) and inducible nitric oxide synthase (iNOS) levels/expression, indicating reduction in the inflammatory damage of the sciatic nerve. Apart from these effects, JSH-23 also increased Nrf2 and hemeoxygenase-1 (HO-1) levels which could imply its potential in increasing the strength of antioxidant defence. CONCLUSION We observed that NF-κB inhibition partially reversed functional, behavioural and biochemical deficits with JSH-23 treatment. This study substantiates the role of NF-κB activation in the aetiology of diabetic neuropathy and protection afforded by inhibition of NF-κB by JSH-23, which can be attributed to its effect on neuroinflammation and oxidative stress.
Collapse
Affiliation(s)
- A Kumar
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India
| | | | | |
Collapse
|