GLP1 secretagogue cinnamaldehyde upregulates GLP1/PI3K/AKT and Nrf2 pathways to exert neuroprotection in a rotenone induced mouse model of Parkinson's disease

Kirti Mathur; Ritu Soni; Ruchi Yadav; Bhumika D Patel; Jigna Shah

doi:10.1016/j.ijbiomac.2025.145733

GLP1 secretagogue cinnamaldehyde upregulates GLP1/PI3K/AKT and Nrf2 pathways to exert neuroprotection in a rotenone induced mouse model of Parkinson's disease

Int J Biol Macromol. 2025 Jul 3;320(Pt 1):145733. doi: 10.1016/j.ijbiomac.2025.145733. Online ahead of print.

Authors

Kirti Mathur¹, Ritu Soni¹, Ruchi Yadav², Bhumika D Patel², Jigna Shah³

Affiliations

¹ Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India.
² Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India.
³ Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India. Electronic address: jigna.shah@nirmauni.ac.in.

PMID: 40615002
DOI: 10.1016/j.ijbiomac.2025.145733

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The progressive pathology of PD leads to depletion of dopaminergic neurons. Alpha-synuclein accumulation is the fundamental cause of the pathology. Hence, in this study, we aim to target alpha-synuclein aggregation by treatment with cinnamaldehyde. Initially, binding affinity and stability of cinnamaldehyde was assessed through in silico studies. In present study, cinnamaldehyde (50 mg/kg p.o.) with rotenone (30 mg/kg p.o.) was administered in C57/BL6 mice for 28 days. At the end of the study, behavioural studies were performed. Also, levels of molecular proteins and oxidative stress markers were estimated. Histopathological studies and immunohistochemistry were also performed. Cinnamaldehyde showed good binding affinity and stable complex with all three protein targets GPR40 (involved in GLP1 secretion), PI3K and Keap1. It was observed that cinnamaldehyde restored behavioural deficits and upregulated levels of GLP1, PI3K, AKT, Nrf2, CREB, BDNF, TH. It downregulated NF-κB and alpha-synuclein levels. It also modulated oxidative stress markers. Moreover, neuronal density and TH+ neuronal density were restored upon treatment with cinnamaldehyde. In conclusion, we can say that cinnamaldehyde exerts neuroprotective action by upregulating GLP/PI3K/AKT and Nrf2 cascades against rotenone induced toxicity in a mouse model of PD.

Keywords: Alpha-synuclein aggregation; Cinnamaldehyde; GLP1; Parkinson's disease; Rotenone.