OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

Abstract

Summary Objective An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ‐aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA‐metabolizing enzyme GABA aminotransferase (GABA‐AT). GABA‐AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA‐AT inactivator than vigabatrin, an antiseizure drug approved as an add‐on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. Methods We therefore examined the effects of OV329 (5, 20, and 40 mg/kg ip) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole (ivPTZ) seizure threshold model as a seizure test particularly sensitive to GABA‐potentiating manipulations, and amygdala‐kindled rats as a model of difficult‐to‐treat temporal lobe epilepsy. Results GABA‐AT inactivation by OV329 clearly increased the threshold of both ivPTZ‐induced and amygdala‐kindled seizures. OV329 further showed a 30‐fold greater anticonvulsant potency on ivPTZ‐induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously. Notably, all rats were responsive to OV329 in both seizure models. Significance These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies.

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development

“…In the intravenous PTZ seizure threshold test model, a single dose of OV329 (5, 20, and 40 mg/kg ip) was given 6 h before PTZ infusion. OV329 at 40 mg/kg resulted in increased seizure threshold, with lower doses having no significant effects 31 . Models characterized by gradual epileptogenesis developing over weeks were also sensitive to the antiseizure effects of OV329.…”

“…OV329 has shown antiseizure effects in multiple distinct rodent seizure or epilepsy models. OV329 shows antiseizure activity in acute models such as the intravenous PTZ seizure threshold test in rats 31 and the N‐methyl‐D‐aspartate mouse model of infantile spasms 32 . In the intravenous PTZ seizure threshold test model, a single dose of OV329 (5, 20, and 40 mg/kg ip) was given 6 h before PTZ infusion.…”

“…In these subacute models, including the amygdala‐kindled rat model 31 and the intrahippocampal kainite mouse model of MTLE, 33 a single high dose of OV329 produced near complete protection from seizure activity. In the amygdala‐kindled chronic model in rats, OV329 increased the seizure threshold after single injections of 30 and 40 mg/kg ip 31 . In the intrahippocampal kainate mouse model of MTLE, OV329 was administered by mouth (.01, .1, 1.0, or 10 mg/kg) or intraperitoneally (10 mg/kg) as a single dose given 4 weeks following kainate injection and the development of epileptogenesis 33 .…”

“…Models characterized by gradual epileptogenesis developing over weeks were also sensitive to the antiseizure effects of OV329. In these subacute models, including the amygdala‐kindled rat model 31 and the intrahippocampal kainite mouse model of MTLE, 33 a single high dose of OV329 produced near complete protection from seizure activity. In the amygdala‐kindled chronic model in rats, OV329 increased the seizure threshold after single injections of 30 and 40 mg/kg ip 31 .…”

A Nucleophilic Activity‐Based Probe Enables Profiling of PLP‐Dependent Enzymes

“…FDA-approved drugs such as vigabatrin, [5] carbidopa, [6] d-cycloserine (DCS), [7] and eflornithine [8] are used to treat patients with epilepsy, Parkinson's disease, tuberculosis, and African sleeping sickness respectively. Moreover, drug discovery efforts are ongoing for numerous PLP-DEs in oncology, infectious disease, and neuroscience, [9][10][11] exemplifying the breadth that these enzymes are used in biology.…”