Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid‐induced seizures in rats

Abstract

Kainic acid (KA)-induced status epilepticus (SE) is a well-characterized model of excitotoxic neuronal injury. Excitotoxicity results from activation of specific glutamate receptors, with resultant elevation of intracellular Ca(2+). The CA1 and CA3 subregions of the hippocampus are especially vulnerable to KA, and this pattern of neuronal injury resembles that occurring in patients with temporal lobe epilepsy. Calcium plays an essential role in excitotoxicity, and accordingly calcium channel inhibitors have been shown to have protective effects in various experimental models of epilepsy and brain injury. Moreover, they also potentiate the antiseizure efficacy of conventional antiepileptic drugs. This study was undertaken to determine whether NP04634, a novel compound, reported as a non-L-type voltage-sensitive calcium channel (VSCC) inhibitor, could prevent the entrance in SE and the neuronal loss evoked by intraperitoneal injection of KA. Our results show that intragastrical administration of NP04634 reduced the percentage of rats that entered SE after KA injection, increased the latency of SE entry, and significantly reduced the mortality of rats that entered SE. Also, NP04634 prevented the loss of hippocampal CA1 and CA3 pyramidal neurons and reduced the gliosis induced by KA. These results point to a potential anticonvulsant and neuroprotective role for NP04634.

Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

“…The pellet was resuspended in culture media (MEM supplemented with 10% FBS, 10% HS, glucose 1 g/l glutamine 2 mM, sodium pyruvate 1 mM, non-essential aminoacids 100 µM, penicillin 50 U/ml and streptomycin 50 µg/ml), and cells seeded onto 24-well plates (5×10 5 cells/well) or 96-well plates (1×10 5 cells/well). After 1 week in culture, cells were treated with LPS (1 µg/ml) [53], [54], [55] or 6-OHDA (35 µM, Sigma), alone or in combination with S14 (10 µM). The effective dose of S14 was determined based on previous studies on EC50 [22].…”

Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

“…Neuronal integrity and specifically the extension of dopaminergic cell death was performed by counting Nissl-stained and TH-positive cells, respectively, in the SNpc in 5 well-defined high magnification (Â400) fields per animal, using a computer-assisted image analysis software (Soft Imaging System Corp). The extent of gliosis was quantified as previously described (Morales-Garcia et al, 2009). …”

Kainic Acid-Induced Neurotoxicity: Targeting Glial Responses and Glia-Derived Cytokines

“…There is increasing realization that the mitochondrial dysfunction occupies the center stage in these processes [28, 29]. In many cell types, glutamate neurotoxicity is induced by NMDA as well as non-NMDA receptors [25, 26, 30]. …”

“…The hilar neurons are sensitive to KA-induced neurotoxicity, but neuron loss in the other areas of the hippocampus differs between animal species and strains [38-40]. In rats, the systemic injections of KA produced widespread neuronal death, primarily in the hippocampus hilus, CA1 and CA3 areas [30, 41]. Mouse strains vary significantly in their sensitivity to KA-induced neurodegeneration [39, 40, 42, 43].…”