title: Mechanism of synapse redox stress in Okadaic acid (ICV) induced memory impairment: Role of NMDA receptor.
abstract: The N-methyl-D-aspartate (NMDA) receptor is a subtype of ionotropic glutamate receptor that is involved in synaptic mechanisms of learning and memory, and mediates excitotoxic neuronal injury. In this study, we tested the hypothesis that NMDA receptor subunit gene expression is altered in cortex and hippocampus of OKA induced memory impairment. Therefore in the present study, we checked the effect of OKA (ICV) on NMDA receptor regulation and synapse function. The memory function anomalies and synaptosomal calcium ion (Ca(2+)) level were increased in OKA treated rats brain; which was further protected by MK801 (0.05mg/kg. i.p) treatment daily for 13days. To elucidate the involvement of NMDA receptor, we estimated NR1, NR2A and NR2B (subunits) expression in rat brain. Results showed that expression of NR1 and NR2B were significantly increased, but expression of NR2A had no significant change in OKA treated rat brain. We also observed decrease in synapsin-1 mRNA and protein expression which indicates synapse dysfunction. In addition, we detected an increase in MDA and nitrite levels and a decrease in GSH level in synapse preparation which indicates synapse altered redox stress. Moreover, neuronal loss was also confirmed by nissl staining in periventricular cortex and hippocampus. Altered level of oxidative stress markers along with neuronal loss confirmed neurotoxicity. Further, MK801 treatment restored the level of NR1, NR2B and synapsin-1 expression, and protected from neuronal loss and synapse redox stress. In conclusion, Okadaic acid (OKA) induced expression of NR1 and NR2B deteriorates synapse function in rat brain which was confirmed by the neuroprotective effect of MK801.
authors.affiliation: Division of Physiology and Biophysics, University of Louisville, KY 40202, USA.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Kamat
authors.affiliation: Division of Pharmacology and Toxicology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India.
authors.forename: Shivika
authors.initials: S
authors.lastname: Rai
authors.affiliation: Scripp Institute, Jupiter, Department of Neuroscience, FL 33458, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Swarnkar
authors.affiliation: Division of Pharmacology and Toxicology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
authors.affiliation: Division of Pharmacology and Toxicology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India. Electronic address: cnathcdri@rediffmail.com.
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
mesh_terms: D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects; D017931:DNA Primers; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism; D019319:Okadaic Acid / Q000008:administration & dosage / Q000633:toxicity*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D016291:Dizocilpine Maleate
keywords: NMDA receptor; Neurotoxicity; Okadaic acid; Synaptic toxicity