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The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Methylphenidate (MPH) abuse has been criticized for its role in neurodegeneration. Also, a high risk of seizure was reported in the first month of MPH treatment. Topiramate, a broad-spectrum Antiepileptic Drug (AED), has been used as a neuroprotective agent in both aforementioned complications. Nanotechnology is introduced to increase desirable neurological treatment with minimum side effects. We aimed to investigate the potential neuroprotective activity of topiramate loaded on nanoparticles., Methods and Results: MTT assay was performed to evaluate the cellular cytotoxicity of Mesoporous Silica Nanoparticles (MSN). Male rats were randomly divided into eight groups. Rats received an intraperitoneal (i.p) MPH (10 mg/kg) injection and a daily oral dose of topiramate (TPM, 30 mg/kg), MSN with Zn core (10 and 30 mg/kg), and MSN with Cu core (10 and 30 mg/kg) for three weeks. On day 21, a seizure was induced by a single injection of pentylenetetrazole (PTZ) to evaluate the protective effects of TPM-loaded nanoparticles on seizure latency and duration following MPH-induced neurotoxicity. Moreover, the hippocampal content of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and the anti-oxidant enzymes (SOD, GPx, and GR) activities were assessed. Also, BAX and Bcl-2 as two main apoptotic markers were evaluated., Results: MPH neurotoxicity was observed as a raised duration and reduced latency in PTZ-induced seizure. However, TPM-loaded MSN with Zn species (NE) treatment reduced the duration and improved the latency time. Also, NE and, somewhat, TPM-loaded MSN with Cu species (NM) administration reduced inflammatory cytokines, MDA, and Bax levels and increased activities in the rat hippocampus., Conclusion: TPM-loaded nanoparticles could be used as neuroprotective agents against MPH-induced neurodegeneration by improving seizure parameters and reducing inflammatory, oxidant, and apoptotic factors., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Rationale: Topiramate, an approved antiepileptic drug, was found effective in treating aggressive symptoms in humans and rodents. However, the effects and mechanisms of Topiramate on aggressive behavior are still unclear. Our previous study indicated that intraperitoneal administration of Topiramate successfully decreased aggression and reinforced sociability in socially aggressive mice, and increased cFos-expressing neurons in the anterior cingulate cortex (ACC). In addition to its pharmacological properties, previous studies have approved the neuroprotective effects of Topiramate. These suggest a potential effect of Topiramate on ACC's structure and function., Objectives and Results: In the present study, we first investigated the structural characteristics of ACC in the social isolation-induced aggression paradigm. The results showed that hyper-aggressive behavior in socially aggressive mice was associated with several structural alterations in ACC: increased neuron death combined with decreased neuron density, increased damaged neuronal morphology and increased neuroinflammation markers. Based on these observations, we next investigated the potential neuroprotective effect of Topiramate against structural alterations of ACC observed in socially aggressive mice. Results indicated that intraperitoneal administration of Topiramate (30 mg/kg) decreased aggression and enhanced sociability without affecting locomotor activity. Interestingly, the anti-aggressive effect of Topiramate was associated with decreased neuronal death, ameliorated damaged neuronal morphology, and decreased reactive microglia markers in ACC., Conclusions: Our results provide insights into the structural alterations of ACC in aggressive socially aggressive mice. Moreover, the present study suggested that the anti-aggressive effect of Topiramate could be related to its neuroprotective effects against the structural alterations of ACC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Topiramate is an approved antiepileptic drug clinically used to treat epilepsy and prevent migraines. Currently, topiramate has been found to be effective in treating aggressive symptoms in neuropsychiatric patients. In preclinical studies, however, the effects and mechanisms of topiramate on offensive aggression are still largely uninvestigated. Our previous studies indicated that glutamatergic transmission in the ventrolateral periaqueductal gray (vlPAG) plays a crucial role in regulating elements of offensive aggressive behaviors. In the present work, we investigated the actions of topiramate on vlPAG glutamatergic transmission and aggressive behaviors in group-housed (GH) and socially isolated (SI) rats. The results suggested that a single injection of topiramate systemically and dose-dependently inhibited elements of offensive aggressive behaviors of both GH and SI rats in the resident-intruder test (RIT), with long-lasting effective time profiles in SI rats. Moreover, systemic single administration of topiramate reduced the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Bath perfusion of topiramate directly decreased the frequency and amplitude of mEPSCs and shortened the amplitude of evoked excitatory postsynaptic currents (EPSCs) in the vlPAG. Furthermore, intra-vlPAG single microinjection of topiramate dose-dependently inhibited offensive aggressive behaviors in GH and SI rats in a time-dependent manner. Additionally, both systemic and local topiramate inhibited offensive aggressive behaviors in a (2R,6R)-hydroxynorketamine (HNK)-dependent rat model. In conclusion, the present results suggest that topiramate exerts anti-aggressive roles through its inhibitory actions on glutamatergic activities in the vlPAG. These preclinical results support topiramate as a candidate drug to treat patients with heightened offensive aggression., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM's anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM's anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1β, IL-1β; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.

Oxaliplatin (OHP) Induced Peripheral Neurotoxicity (OIPN) is one of the dose-limiting toxicities of the drug and these adverse effects limit cancer therapy with L-OHP, used for colorectal cancer treatment. Acute neurotoxicity consists of symptoms that are the hallmarks of a transient axonal hyperexcitability; chronic neurotoxicity has a clinical picture compatible with a length-dependent sensory neuropathy. Acute OIPN pathogenesis has been linked to sodium voltage-operated channels (Na + VOC) dysfunction and it has been advocated as a possible predisposing factor to chronic neurotoxicity. We tested if topiramate (TPM), a well-known Na + VOC modulator, was able to modify acute as well as chronic OIPN. The project was divided into two parts. In Experiment 1 we tested by means of Nerve Excitability Testing (NET) a cohort of female Wistar rats to assess TPM effects after a single OHP administration (5 mg/kg, iv). In Experiment 2 we assessed TPM effects after chronic OHP treatment (5 mg/kg, 2qw4ws, iv) using NET, nerve conduction studies (NCS), behavioral tests and neuropathology (caudal nerve morphometry and morphology and Intraepidermal Nerve Fiber [IENF] density). In Experiment 1 TPM was able to prevent OHP effects on Na + VOC: OHP treatment induced a highly significant reduction of the sensory nerve's threshold, during the superexcitability period (p-value = 0.008), whereas TPM co-administration prevented this effect. In Experiment 2 we verified that TPM was able to prevent not only acute phenomena, but also to completely prevent chronic OIPN. This latter observation was supported by a multimodal approach: in fact, only OHP group showed altered findings compared to CTRL group at a neurophysiological (proximal caudal nerve sensory nerve action potential [SNAP] amplitude, p-value = 0.001; distal caudal nerve SNAP amplitude, p-value<0.001, distal caudal nerve sensory conduction velocity, p-value = 0.04), behavioral (mechanical threshold, p-value 0.003) and neuropathological levels (caudal nerve fibers density, p-value 0.001; IENF density, p-value <0.001). Our data show that TPM is a promising drug to prevent both acute and chronic OIPN. These findings have a high translational potential, since they were obtained using outcome measures that match clinical practice and TPM is already approved for clinical use being free from detrimental interaction with OHP anticancer properties., (Copyright © 2019 Elsevier Ltd. All rights reserved.)