Brivaracetam does not alter spatial learning and memory in both normal and amygdala-kindled rats

Detrait, Eric; Leclercq, Karine; Löscher, Wolfgang; Potschka, Heidrun; Niespodziany, Isabelle; Hanon, Étienne; Kamiński, Rafał M.; Matagne, Alain; Lamberty, Yves

doi:10.1016/j.eplepsyres.2010.06.014

Cited by 22 publications

(22 citation statements)

References 29 publications

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“…However, in an amygdala‐kindling model of temporal lobe epilepsy, BRV, administered at doses that exerted pronounced anticonvulsant effects in fully kindled rats, did not negatively impact hippocampal‐dependent spatial learning and memory performance in the Morris water‐maze test; an effect that was also demonstrated in normal rats (Fig. S5) …”

Section: Adverse Effectsmentioning

confidence: 85%

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Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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SUMMARYDespite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

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Section: Adverse Effectsmentioning

confidence: 85%

“…This result was further substantiated by the lack of impact of BRV on long‐term potentiation (LTP) in hippocampal slices . LTP is a widely used paradigm to investigate methods of synaptic plasticity, memory formation, and consolidation.…”

Section: Adverse Effectsmentioning

confidence: 97%

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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“…Brivaracetam had no negative impact on cognitive performance in both normal and kindled animal models and on long-term potentiation in hippocampal slices, suggesting hippocampal-dependent cognitive function is not adversely affected (Detrait et al, 2010).…”

Section: Pharmacologymentioning

confidence: 99%

Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII)

et al. 2015

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“…The Morris water maze (MWM; Morris, 1984) is one such well-validated rodent model of learning (Wenk, 2004) that is highly translatable to the clinical setting because patients with hippocampal lesions also demonstrate deficits in cognitive performance in tasks similar to the rodent MWM (Bohbot et al, 1998). The assessment of cognitive performance in the MWM in the preclinical arena can follow a neurological insult, i.e., post pilocarpine-induced SE (Cunha et al, 2009;White et al, 2012), post-TBI (Dash et al, 2010), or simply the effect of an investigational agent on naive or chronically diseased animals (Detrait et al, 2010).…”

Section: Predicting Tolerability To Therapies Through Preclinical Evamentioning

confidence: 98%

How Clinical Development Can, and Should, Inform Translational Science

Barker‐Haliski

Friedman²,

White

et al. 2014

Neuron

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There is an urgent need for preclinical translational efforts to be realized as breakthroughs in therapy for the many patients with life-altering conditions affecting the CNS. Despite intensive efforts, few transformative therapies have emerged, and many new potential therapies that looked promising in preclinical development have failed in the clinic. In this Perspective, we suggest that if preclinical scientists partner early with clinical scientists, they can begin to envision the pathway forward for their work through clinical trials. Options might include determining the populations to be treated, issues of dose selection, timing of intervention, duration of intervention, and the availability of biomarkers. In addition, understanding other factors that impact the likelihood that a proof-of-concept trial can be performed, as well as other critical issues, will altogether increase the attractiveness of the project to investors and partners and will also increase the likelihood that the intervention will succeed in the clinic.

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Brivaracetam does not alter spatial learning and memory in both normal and amygdala-kindled rats

Cited by 22 publications

References 29 publications

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII)

How Clinical Development Can, and Should, Inform Translational Science

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