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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.)

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.)

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABA A receptors (α6GABA A Rs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABA A Rs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABA A R-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABA A R-active PAMs (Ro15-4513 and loreclezole), an α6GABA A R-inactive benzodiazepine (diazepam), an α6GABA A R-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABA A R in TG is a novel drug target for TGVS activation and that α6GABA A R-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)