title: Activation of AKT/GSK3β pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice.
abstract: 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.
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors.forename: Malay
authors.initials: M
authors.lastname: Bhowmik
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors.forename: Razia
authors.initials: R
authors.lastname: Khanam
authors.affiliation: Institute of Genomics & Integrative Biology (CSIR-IGIB), New Delhi, India.
authors.forename: Neeru
authors.initials: N
authors.lastname: Saini
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India. Electronic address: dvohra@jamiahamdard.ac.in.
authors.forename: Divya
authors.initials: D
authors.lastname: Vohora
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D013830:Thiadiazoles / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D019253:Proto-Oncogene Proteins c-bcl-2; D013830:Thiadiazoles; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D007608:Kainic Acid
keywords: 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8); Apoptosis; Glycogen synthase kinase 3β (GSK3β); Kainic acid (KA); Neurodegeneration