title: Histamine H3 receptor antagonism by ABT-239 attenuates kainic acid induced excitotoxicity in mice.
abstract: 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.
authors: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors: Malay
authors: M
authors: Bhowmik
authors: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors: Neeru
authors: N
authors: Saini
authors: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India. Electronic address: divyavohora@hotmail.com.
authors: Divya
authors: D
authors: Vohora
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D007608:Kainic Acid; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D011897:Random Allocation; D012640:Seizures / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013830:Thiadiazoles / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000927:Anticonvulsants; D001572:Benzofurans; D054828:Histamine H3 Antagonists; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013830:Thiadiazoles; D014635:Valproic Acid; C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D007608:Kainic Acid
keywords: 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile (ABT-239); Histamine H3 receptor (H3R); Kainic acid (KA); Neurodegeneration; Phospho-GSK3β (Ser9, pGSK3β(ser9)); cAMP response element binding protein (CREB)