Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats

Abstract

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington’s disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aβ42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3β and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Targeting Autophagy, Apoptosis, and Oxidative Perturbations with Dapagliflozin Mitigates Cadmium-Induced Cognitive Dysfunction in Rats

“…There was a two-hour interval between the two doses and the treatment protocol lasted for 2 months. The experimental regimen coincides with previously reported studies [22][23][24][25][26].…”

Cadmium neurotoxicity and therapeutic strategies

“…[ 123 ] Topiramate has also been reported to induce autophagy by inhibiting the mTOR pathway, hence alleviating hippocampal damage in Cd‐intoxicated rats. [ 124 ]…”

“…PC12 cell line and mouse cortical neuron CdCl 2 , 10 and 20 μM Resveratrol, 100 μM Liu et al [123] Rat cerebral cortical neuron CdAc 2 , 20 μM Rapamycin, 100 nM Wang et al [119] Rat CdCl 2 , 5 mg/kg bw Topiramate, 50 mg/kg bw Arab et al [124] Abbreviations: bw, body weight; CdAc 2 , cadmium acetate; CdCl 2 , cadmium chloride; CNS, central nervous system.…”

“…[123] Topiramate has also been reported to induce autophagy by inhibiting the mTOR pathway, hence alleviating hippocampal damage in Cdintoxicated rats. [124] Mitophagy, a process involving the selective and targeted degradation of mitochondria by autophagy, [125] is particularly important to neurons as this cell type always requires high energy production levels. Mitochondria are the primary site for energy production and the primary origin of ROS within cellular systems.…”