Modulation of Kainate-Induced Excitotoxicity in Rats

Jones, Paul A (1998) Modulation of Kainate-Induced Excitotoxicity in Rats. PhD thesis, University of Glasgow.

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Kainic acid has been used widely as an effective model of excitotoxic neurodegeneration. Using both the intraperitoneal and intrahippocampal routes of injection, we have shown that kainate selectively damages discrete populations of cells in the hippocampus. Following intraperitoneal administration, the A2A agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) and N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA), protected against kainate-induced cell death. Protection by CGS 21680 was slightly moderated by the Ai receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX), but substantially reduced by the addition of the peripherally acting adenosine antagonist 8-(p-sulphophenyltheophylline) (8-PST). The administration of a selective A2A antagonist 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo {2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM 241385) also protected the hippocampus against kainate toxicity. This protection was reversed when ZM 241385 was co-administered with CPX. After intrahippocampal injections of kainate, neither CGS 21680, R-phenylisopropyladenosine (R-PIA) nor adenosine were protective in the CA3a region of the hippocmpus. ZM 241385 decreased kainate-induced neuronal death, as did the addition of the NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine maleate (MK-801). Combined results from both intrahippocampal and intraperitoneal studies, suggested that protection by the A2A agonist was mediated mostly from the periphery and not from receptors localised within the hippocampus. Evidence also suggested that stimulation of A2A receptors resulted in an inhibition of the A1 subtype. Importantly, this study questioned the previous assumption that adenosine, released endogenously during cerebral insults, mediates protection. The nitric oxide synthesis inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), also protected against intraperitoneally administered kainate. This suggested that inhibition of neuronally (and not endothelially) produced nitric oxide was beneficial. Studies using the TdT-mediated dUTP-biotin nick end labelling (TUNEL) method for identifying apoptotic cells showed that following intraperitoneal kainate administration, apoptosis was localised to the CAl region of the hippocampus. Expression of the brain-derived neurotrophic factor (BDNF) protein was investigated, and a possible link between the mechanism of cell death and the inflammatory response also examined.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Trevor Stone
Keywords: Neurosciences, Toxicology
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-75938
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 17:14
Last Modified: 19 Nov 2019 17:14

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