Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats

Abstract

Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D receptor antagonist. Open field test (OFT) was used to investigate the disturbances in motor activity. Hippocampal neurodegenerative parameters were evaluated. Protein expressions of CREB/BDNF and Akt/GSK3 signaling pathways were also evaluated. Cresyl violet staining was performed to show and confirm the changes in the shape of the cells. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased Bcl-2 expression, the level of reduced form of glutathione (GSH) and the levels and activities of superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes. TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing CREB, BDNF and Akt protein expressions. Also pretreatment with DOM, BIC, KET and YOH inhibited TPM-induced decreases in GSK3. It can be concluded that the mentioned receptors by modulation of CREB/BDNF and Akt/GSK3 pathways, are involved in neuroprotection of TPM against MPH-induced neurodegeneration.

Tannins from Terminalia chebula fruits attenuates GABA antagonist-induced anxiety-like behaviour via modulation of neurotransmitters

“…Studies have shown that activated CREB or P-CREB involvement in a variety of functional responses associated with nervous system. [40] Previous reports have confirmed that CREBdependent BDNF expression has a major role in neuronal development, neurogenesis and mood disorders such as anxiety and depression. [41] In this study, PTX had downregulated CREB, p-CREB and BDNF expressions significantly when compared to the control animals (P < 0.05).…”

“…Based on these observations, it can be assumed that TCHE ameliorated PTX‐induced anxiety through modulating serotonergic, dopaminergic and noradrenergic systems. Studies have shown that activated CREB or P‐CREB involvement in a variety of functional responses associated with nervous system . Previous reports have confirmed that CREB‐dependent BDNF expression has a major role in neuronal development, neurogenesis and mood disorders such as anxiety and depression .…”

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic–clonic seizure model in mice

“…Recommendations may include drugs that also block calcium channels in neurons and thus, inhibit presynaptic liberation of excitatory neurotransmitters in neurons (PGB) [29]. Besides, favorable combinations of AEDs were reported for the drugs exerting several molecular mechanisms of action (i.e., with multi-targets of their anticonvulsant activity-TPM) [43][44][45]. From a theoretical point of view, the most recommended combinations should consist of PB or one of the GABA A -receptor activating drugs, LTG or OXC -or one of the sodium channel blockers, which inhibits seizure propagation in the brain and one of the multi-targets drugs like TPM, with various molecular mechanisms of action.…”

Neuroprotective Effects of Forced Exercise and Bupropion on Chronic Methamphetamine-induced Cognitive Impairment via Modulation of cAMP Response Element-binding Protein/Brain-derived Neurotrophic Factor Signaling Pathway, Oxidative Stress, and Inflammatory Biomarkers in Rats

“…Finally, the absorbance was read at 532 nm, and the results obtained were expressed as nmol/mg of protein. [3282935363738]…”

“…[12] Glycogen synthase kinase-3-beta (GSK3β) is an important intracellular regulatory protein that is subject to phosphorylation by growth factor-stimulated signaling pathways (such as BDNF). [34] GSK3β is inhibited upon serine 9-phosphorylation by growth factor receptor-induced activation of Akt. [5] GSK3β is a protein kinase that has important regulatory effects in neural plasticity and survival.…”