In vivo electrophysiological experiments were conducted to evaluate the effects of intraventricular and cortical administration of orexins on electrically evoked epileptiform discharges (EEDs) in the hippocampal CA1 field. Bipolar electrodes were stereotaxically implanted into the CA1 region of anesthetized rats, and epileptiform activity was induced by high‑frequency electrical stimulation (HFES). Orexin‑A and orexin‑B (10 μg/10 μl) were administered into the lateral ventricle or applied to the frontal cortex. Intracerebroventricular administration of orexin‑A significantly reduced the duration of EEDs within 20 minutes and abolished the progressive, HFES‑related prolongation of epileptiform discharges observed in control animals. In contrast, cortical administration of orexin‑A selectively reduced the incidence of high‑amplitude (7-10 mV) population spikes during EEDs without affecting the duration of epileptiform activity. Neither cortical nor intraventricular administration of orexin‑B produced significant changes in evoked epileptiform activity in the CA1 field, suggesting a possible involvement of OX1 receptor signaling in mediating the effects of orexin‑A. The differential effects observed after cortical versus intraventricular administration of orexin‑A appear to reflect site‑specific mechanisms of action. The effects of intraventricular administration of orexin‑A were predominantly induced via direct activation of hippocampal orexinergic receptors, whereas cortical application of orexin‑A induced its effects via modulation of cortico‑hippocampal mechanisms.
Proton pump inhibitors are widely used, but their long‑term effects on the central nervous system are not well understood. In this study, we investigated whether chronic pantoprazole use alters sensorimotor function, oxidative stress, inflammatory response, and apoptosis in the motor cortex and cerebellum. Twenty‑one female Wistar rats were randomized to control (C), gavage control (GC), or pantoprazole (P; 20 mg/kg/day for 12 weeks) groups. Sensorimotor coordination (rotarod), water‑maze swim velocity, and open‑field locomotion were assessed as behavioral parameters. The cortical and cerebellar tissues were analyzed by Enzyme‑Linked Immunosorbent Assay (ELISA) for apoptosis, inflammation, and oxidative stress. Pantoprazole impaired sensorimotor coordination compared to both control groups. However, its effects on swim velocity and locomotor activity were primarily significant when compared to the naive control group, suggesting that gavage‑related stress may have contributed to these behavioral outcomes. Bcl‑2‑associated X protein (BAX) and Bcl‑2 associated agonist of cell death (BAD) protein levels and the BAX/Bcl‑2 ratio increased with pantoprazole, particularly in the motor cortex, indicating enhanced pro‑apoptotic activity. While tumor necrosis factor levels did not change, interleukin (IL)‑6 and IL‑1β levels were significantly higher in the cerebellum, suggesting neuroinflammatory activation associated with both pantoprazole and gavage‑induced stress. Furthermore, oxidative stress analyses revealed elevated malondialdehyde and oxidative stress index levels, as well as increased total antioxidant status, in specific regions, suggesting an imbalance between oxidative and antioxidant responses. Chronic pantoprazole administration resulted in modest motor deficits and region‑specific molecular alterations, including a pro‑apoptotic shift in the motor cortex. In addition, an inflammatory/compensatory antioxidant response in the cerebellum was observed due to both gavage‑induced stress and pantoprazole administration. These findings highlight the need for further studies on dose‑response, reversibility, and synaptic consequences, and suggest the importance of considering the risks of prolonged proton pump inhibitors exposure.
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) affecting millions worldwide, leading to significant disability. Current treatments focus on symptom management and reducing disease exacerbations. Noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) have emerged as potential therapies due to their ability to modulate cortical excitability and neuroplasticity. This review explores the therapeutic potential of tDCS in MS patients by summarizing human and animal studies investigating its effects. Literature was systematically reviewed from inception to October 2024 using PubMed and Google Scholar databases. Key findings include tDCS's ability to alleviate symptoms such as pain, fatigue, cognitive impairment, and motor dysfunction in MS patients. Mechanistically, tDCS is proposed to influence neurotransmitter modulation, inflammatory pathways, and neuronal networks, promoting neuroprotection and functional recovery. Moreover, preclinical studies in MS animal models suggest that tDCS may reduce inflammation, promote remyelination, and enhance neuronal survival. These insights underscore tDCS as a promising adjunctive therapy for MS, potentially improving quality of life and mitigating disease progression. Further research is warranted to elucidate optimal stimulation parameters, long‑term effects, and broader applicability in clinical settings.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. The G2019S mutation in the leucine‑rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of familial and sporadic PD. In dopaminergic neurons, increased kinase activity caused by LRRK2‑G2019S mutation impairs synaptic vesicle recycling and dopamine storage, increasing cytosolic dopamine, which is prone to oxidation and generates reactive oxygen species. Simultaneously, the mutation alters iron metabolism through Rab misregulation, increasing iron uptake and lysosomal dysfunction, further amplifying oxidative stress and creating a pro‑ferroptotic environment. At the same time, dysregulated calcium signaling, driven by the enhanced activity of L‑type calcium channels and impaired mitochondrial calcium buffering via the mitochondrial calcium uniporter, enhances mitochondrial dysfunction. This minireview integrates current evidence linking LRRK2‑G2019S to these pathological pathways, highlighting this mutation's role in dopamine, iron, and calcium imbalance. Understanding this molecular interplay may provide novel insights into PD pathogenesis and guide the development of targeted neuroprotective therapies.
Scopolamine, a muscarinic acetylcholine receptor antagonist, disturbs learning and memory processes. Clozapine, an atypical antipsychotic, has beneficial predictive validity for confirming principles to help new treatment approaches. It could improve the cognitive deficit. Furthermore, clozapine has affinity for the cholinergic and GABAergic receptors. This investigation examined the effects of clozapine and/or GABAA receptor drugs on scopolamine‑induced memory impairment in male mice. Step‑down passive avoidance and open‑field tests were utilized for assessing memory acquisition and locomotor activity, respectively. The results exhibited that pre‑training administration of muscimol but not bicuculline induced amnesia without affecting locomotor activity. Moreover, pre‑training administration of clozapine did not significantly modify memory acquisition, but co‑administration of scopolamine and clozapine improved the amnesia produced with scopolamine. Also, co‑administration of muscimol along with clozapine potentiated memory impairment induced by scopolamine, whereas co‑injection of bicuculline along with clozapine reversed memory impairment produced by scopolamine. These treatments did not significantly change locomotor activity. Based on the findings, it is concluded that the GABAergic system modulates memory acquisition, and clozapine interacts with both muscarinic and GABAergic systems to bidirectionally regulate scopolamine‑induced amnesia. These results suggest the potential involvement of GABAergic mechanisms in the memory‑impairing effects of scopolamine and highlight the therapeutic potential of clozapine in mitigating cholinergic dysfunction‑related memory deficits.
