4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Seizures

Activation of glycogen synthase kinase3β (GSK3β), an enzyme that regulates a multitude of cellular signaling pathways, is implicated in neurodegenerative processes observed in an array of CNS diseases. We examined the hypothesis that the pathological changes in an acute kainic acid (KA) induced excitotoxicity model, relevant to human temporal lobe epilepsy (TLE), could be sensitive to inhibition of GSK3β by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) treatment in Swiss albino mice. Immediate seizure responses due to KA were recorded. Neurodegenerative and morphogenic changes were examined by western blot analysis and light microscopy, respectively, 48 h after KA administration. Although tonic-clonic seizure episodes evoked by KA were unaffected, TDZD-8 pretreatment decreased KA mediated elevation in caspase-3 cleavage as well as increased Bcl2 and phospho-GSK3β (Ser9; pGSK3β(Ser9)) expression. Likewise, microscopic examination also revealed that pretreatment with TDZD-8 attenuated cell damage elicited by KA in the CA1, CA3 and DG regions. In all the above parameters, the combined effect of a sub-effective dose of sodium valproate (SVP) with TDZD-8 was higher than that of solitary TDZD-8 treatment. The findings suggest that activated GSK3β orchestrated neurodegenerative alterations following KA treatment and its inhibition by TDZD-8 affords a distinct neuroprotective profile by activating Akt/GSK3β pathway which might act upstream of Bax/Bcl2 and caspase-3 pathways. Compounds targeting GSK3β activity might represent a novel therapeutic option for exploration as an adjunct to conventional anti-epileptic drugs in preventing neurodegenerative processes in TLE.

Topics: Analysis of Variance; Animals; bcl-2-Associated X Protein; Brain; Caspase 3; Disease Models, Animal; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Kainic Acid; Male; Mice; Neurodegenerative Diseases; Oncogene Protein v-akt; Proto-Oncogene Proteins c-bcl-2; Seizures; Signal Transduction; Thiadiazoles

The multifaceted pathogenesis of temporal lobe epilepsy (TLE) offers a number of adjunctive therapeutic prospects. One such therapeutic strategy could be targeting H3 receptor (H3R) by selective H3R antagonists which are perceived to have antiepileptic and neuroprotective potential. Kainic acid (KA) induced seizure, a reliable model of TLE, triggers epileptogenic events resulting from initial neuronal death and ensuing recurring seizures. The present study aimed to determine whether pre-treatment with ABT-239, a novel H3R antagonist, and its combinations with sodium valproate (SVP) and TDZD-8 (glycogen synthase kinase-3β (GSK3β) inhibitor) can prevent the excitotoxic events in mice exposed to KA (10 mg/kg i.p.). ABT-239 (1 and 3 mg/kg i.p.) significantly attenuated KA-mediated behavioural and excitotoxic anomalies and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and cAMP response element binding protein (CREB). Surprisingly, restoration of Bcl2 and phospho-GSK3β (Ser9) by ABT-239 did not reach the level of statistical significance. Co-administration of ABT-239 (1 and 3 mg/kg) with a sub-effective dose of SVP (150 mg/kg i.p.) yielded improved efficacy than when given alone. Similarly, low and high dose combinations of ABT-239 (1 and 3 mg/kg) with TDZD-8 (5 and 10 mg/kg i.p.) produced greater neuroprotection than any other treatment group. Our findings suggests a neuroprotective potential of ABT-239 and its combinations with SVP and TDZD-8 against KA-induced neurotoxicity, possibly mediated through in part each by modulating Akt/GSK3β and CREB pathways. The use of H3R antagonists as adjuvant in the treatment of human TLE might find potential utility, and can be pursued further.

Topics: Animals; Anticonvulsants; Benzofurans; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Histamine H3 Antagonists; Kainic Acid; Male; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Protein Kinase Inhibitors; Pyrrolidines; Random Allocation; Seizures; Thiadiazoles; Valproic Acid