title: A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action.
abstract: In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Sumana
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Maitra
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: R Gajendra
authors.initials: RG
authors.lastname: Reddy
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Tapatee
authors.initials: T
authors.lastname: Das
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Jhelum
authors.affiliation: CSIR- Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, India.
authors.forename: Scherazad
authors.initials: S
authors.lastname: Kootar
authors.affiliation: CSIR- Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, India.
authors.forename: Wenson D
authors.initials: WD
authors.lastname: Rajan
authors.affiliation: Chemical Biology, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Anumita
authors.initials: A
authors.lastname: Samanta
authors.affiliation: Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Samineni
authors.affiliation: Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
authors.forename: Srihari
authors.initials: S
authors.lastname: Pabbaraja
authors.affiliation: Department of Pediatrics and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.affiliation: School of Chemistry, University of Hyderabad, Hyderabad; 500046, India.
authors.forename: Goverdhan
authors.initials: G
authors.lastname: Mehta
authors.affiliation: CSIR- Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, India.
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D055808:Drug Discovery; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000517:prevention & control; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D020813:Receptor, trkB / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015027:Zebrafish
chemical_list: C559317:ANA 12 compound; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D005419:Flavonoids; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one