Proneurogenic and microglial modulatory properties of botulinum neurotoxin in the hippocampus of aging experimental mice

doi:10.5493/wjem.v15.i4.108187

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World Journal of Experimental Medicine

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World J Exp Med. Dec 20, 2025; 15(4): 108187
Published online Dec 20, 2025. doi: 10.5493/wjem.v15.i4.108187

Proneurogenic and microglial modulatory properties of botulinum neurotoxin in the hippocampus of aging experimental mice

Jerly Helan Mary Joseph, Mercy Priyadharshini Babu Deva Irakkam, Mahesh Kandasamy

Jerly Helan Mary Joseph, Mercy Priyadharshini Babu Deva Irakkam, Mahesh Kandasamy, Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India

Mahesh Kandasamy, University Grants Commission-Faculty Recharge Programme, New Delhi 110002, India

Author contributions: Joseph JHM contributed to formal analysis; Kandasamy M and Joseph JHM contributed to writing-original draft; Kandasamy M and Babu Deva Irakkam MP contributed to review; Joseph JHM and Babu Deva Irakkam MP contributed to methodology, acquisition of data, validation; Kandasamy M contributed to conceptualization, project administration, supervision, funding acquisition, data curation, and editing.

Supported by the Science and Engineering Research Board (SERB), No. SERB-EEQ/2016/000639; RUSA 2.0, Biological Sciences, Bharathidasan University, No. TN RUSA: 311/RUSA (2.0)/2018 dt. December 2, 2020; the University Grants Commission, Faculty Recharge Programme (UGC-FRP), New Delhi, India; Council of Scientific and Industrial Research– Senior Research Fellowship (CSIR-SRF)–Direct, No. 09/0475(23353)/2025-EMR-I.

Institutional review board statement: This work was reviewed and approved by the Institutional Animal Ethics Committee (IAEC), Bharathidasan University (Ref No: BDU/IAEC/P27/2018, August 07, 2018), under the regulation of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India.

Institutional animal care and use committee statement: This work was reviewed and approved by the Institutional Animal Ethics Committee (IAEC), Bharathidasan University (Ref No: BDU/IAEC/P27/2018, August 07, 2018), under the regulation of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India.

Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: No additional data are available.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Mahesh Kandasamy, PhD, UGC-Assistant Professor, Laboratory of Stem Cells and Neuroregeneration, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India. mahesh.kandasamy@bdu.ac.in

Received: April 7, 2025
Revised: May 16, 2025
Accepted: August 4, 2025
Published online: December 20, 2025
Processing time: 256 Days and 5.5 Hours

Abstract

BACKGROUND

Botulinum neurotoxin (BoNT) is widely recognized as an effective therapeutic agent for managing various neurological disorders, characterized by motor impairments and neuromuscular deficits. BoNT works by modulating the release of acetylcholine at the neuromuscular junction. Recently, BoNT has been shown to enhance spatial memory and attenuate anxiety in experimental aging animals. While neurogenesis in the hippocampus contributes to cognitive properties, BoNT treatment could potentially influence the regulation of adult neurogenesis. As aging-associated microglial activation impairs neurogenesis, the anti-inflammatory properties of BoNT could be associated with the modulation of microglial activity, thereby enhancing cognitive function.

AIM

To investigate the neurogenic and microglial modulatory properties of BoNT in the hippocampus of aging experimental mice.

METHODS

Experimental aging mice were administered BoNT and after four weeks, the animals were sacrificed. The brains were subjected to cryosections followed by immunohistochemical analysis to quantify doublecortin (DCX)-positive immature neurons, bromodeoxyuridine (BrdU)-neuronal nuclei (NeuN) double positive newly matured neurons and ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia in the hippocampal dentate gyrus. In parallel, an additional set of animals was used to evaluate BoNT-mediated alterations in key inflammatory markers such as cyclooxygenase (COX)-2, and nitric oxide (NO) in hippocampal tissues.

RESULTS

The results revealed a significant increase in the number of DCX-positive immature neurons and BrdU-NeuN positive differentiated neurons in the hippocampus of the BoNT-treated group compared to the control. This enhancement in neurogenesis was accompanied by a marked reduction in the activated form of microglial cells, coupled with decreased mRNA expression of COX-2 and reduced NO levels in the hippocampus of BoNT-treated animals.

CONCLUSION

This study validates the proneurogenic and anti-neuroinflammatory properties of BoNT, which may underlie its procognitive effects. Hence, BoNT could be a promising therapeutic agent for treating various neurocognitive disorders.

Keywords: Botulinum neurotoxin; Doublecortin; Microglia; Neurogenesis; Cyclooxygenase; Nitric oxide; Hippocampus

Core Tip: Botulinum neurotoxin (BoNT) exerts pleiotropic effects, including notable neuroprotection. This study evaluated whether BoNT can ameliorate aging-related neuroinflammation and prevent the decline of hippocampal neurogenesis. BoNT treatment significantly reduced the number of activated microglia, accompanied by decreased expression of cyclooxygenase-2 and diminished levels of nitric oxide. Therefore, the observed increase in doublecortin-positive immature neurons and bromodeoxyuridine - neuronal nuclei double-positive newly generated neurons in the hippocampus may signify the synergistic anti-inflammatory and neuroregenerative properties of BoNT. These findings suggest that BoNT treatment could be explored as a therapeutic agent for the treatment of dementia.