Topiramate Reprofiling for the Attenuation of Cadmium-Induced Testicular Impairment in Rats: Role of NLRP3 Inflammasome and AMPK/mTOR-Linked Autophagy

Abstract

Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric/intestinal injury. However, its potential impact on cadmium-induced testicular injury remains to be elucidated. Herein, the present study aimed to explore the effect of topiramate against cadmium-invoked testicular impairment with emphasis on the molecular mechanisms linked to inflammation, apoptosis, and autophagy. Herein, administration of topiramate (50 mg/kg/day, by gavage) continued for 60 days and the testes were examined by histology, immunohistochemistry, and biochemical assays. The present data demonstrated that serum testosterone, sperm count/abnormalities, relative testicular weight, and histopathological aberrations were improved by topiramate administration to cadmium-intoxicated rats. The rescue of testicular dysfunction was driven by multi-pronged mechanisms including suppression of NLRP3/caspase-1/IL-1β cascade, which was evidenced by dampened caspase-1 activity, lowered IL-1β/IL-18 production, and decreased nuclear levels of activated NF-κBp65. Moreover, curbing testicular apoptosis was seen by lowered Bax expression, decreased caspase-3 activity, and upregulation of Bcl-2. In tandem, testicular autophagy was activated as seen by diminished p62 SQSTM1 accumulation alongside Beclin-1 upregulation. Autophagy activation was associated with AMPK/mTOR pathway stimulation demonstrated by decreased mTOR (Ser2448) phosphorylation and increased AMPK (Ser487) phosphorylation. In conclusion, combating inflammation/apoptosis and enhancing autophagic events by topiramate were engaged in ameliorating cadmium-induced testicular impairment.

Targeting the Endoplasmic Reticulum Stress-Linked PERK/GRP78/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats

“…On the 24th day, anesthesia of the animals was carried out using sodium phenobarbital (150 mg/kg, i.p.) [ 45 ], and blood was withdrawn by an intracardiac puncture for serum separation. Then, euthanization was applied by decapitation and the 2 hippocampi were carefully dissected and stored at −80 °C for the biochemical measurements.…”

Neuroprotective Impact of Linagliptin against Cadmium-Induced Cognitive Impairment and Neuropathological Aberrations: Targeting SIRT1/Nrf2 Axis, Apoptosis, and Autophagy

“…For each experimental group, the mean optical density of either p-AMPK or p-mTOR was divided by the corresponding mean optical density of the total AMPK or total mTOR, respectively. This was followed by setting the mean control value to one [ 53 ]. SQSTM-1/p62 and Beclin1 protein levels were quantified using the SunLong Biotech.…”

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

“…In the current experiments, topiramate instigated hippocampal SQSTM-1/p621 clearance, Beclin1 upregulation, and AMPK/mTOR pathway stimulation, pointing to notable autophagy activation. Indeed, topiramate’s pro-autophagic actions were previously characterized in transgenic mice [ 22 ] and metal-induced testicular deficits [ 39 ]. In neurodegenerative diseases, AMPK/mTOR pathway stimulation is associated with curbing the cognitive deficit and AD neuropathology by the removal of amyloid aggregates and p-tau [ 14 ].…”