title: Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats.
abstract: In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-α indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIα and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-α, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death.
authors: Division of Pharmacology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India.
authors: Shivika
authors: S
authors: Rai
authors: Division of Physiology and Biophysics, University of Louisville, KY 40202, USA.
authors: Pradeep K
authors: PK
authors: Kamat
authors: Division of Toxicology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India.
authors: Chandishwar
authors: C
authors: Nath
authors: Division of Pharmacology, CSIR-Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, U.P. 226001, India. Electronic address: rakeshshuklacdri@gmail.com.
authors: Rakesh
authors: R
authors: Shukla
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology
chemical_list: D017931:DNA Primers; D013311:Streptozocin
keywords: 1-(naphthyl) ethylenediamine dihydrochloride; 2, 7 dichlorofluorescein; 3-[4,5-dimethyl-thiozol-2-yl]-2,5 diphenyl tetrazolium bromide; CamKIIα; DCF; ELT; FURA-2 Acetoxy-methyl ester; FURA-2AM; Free radicals; GFAP; Glial activation; ICV; Intracerebroventricular; MTT; Memory impairment; NEDA; PSD; RNS; ROS; SNAP25; STZ; Streptozotocin; Synaptic markers; aCSF; artificial cerebrospinal fluid; calmodulin kinaseiiα; escape latency times; glial fibric acidic protein; post synaptic density; reactive nitrogen species; reactive oxygen species; synaptosome associated protein