Neuroprotection against excitotoxic cell damage in rat striatum and hippocampus

Arvin, Babak (1989) Neuroprotection against excitotoxic cell damage in rat striatum and hippocampus. University of Southampton, Doctoral Thesis.

Abstract

Injection of excitatory amino acid analogues into the rat striatium produced a marked loss of NADPH-diaphorase (NADPH-d), acetylcholinesterase (AChE) and cresyl violet stained cells. Cell counts for these markers showed approximately a 90% reduction. Injection of kainic acid and quinolinic acid into the rat hippocampus caused a complete loss of pyramidal cells (CAl-CA4) and granule cells of dentate gyrus. Intraventricular (icv) injection of kainic acid caused a selective loss of CA3/CA4 pyramidal cells. Co-injection of NMDA antagonists with quinolinic acid, NMDA, ibotenic acid and glutamic acid in the striatum and hippocampus led to a 80% neuroprotection. Co-injection of an equimolar concentration of AP7 with kainic acid produced neuroprotection in both regions. Lower concentrations of AP7, while able to protect against intrastriatal quinolinic acid toxicity, was unable to protect against kainic acid toxicity. Systemic injection of MK-801 protected against quinolinic acid but not kainic acid toxicity. Co-injection of 2-chloroadenosine (CLAD) and kainic acid produced a dose-dependent protection in rat striatum and hippocampus. This protection was partially reversed with theophylline. Co-injection of CLAD with quinolinic acid only produced a slight protection. Using continuous fluorometry, CLAD was shown to inhibit potassium-evoked endogenous glutamate release in crude synaptosomes and slices. Kainic acid (1mM) failed to promote a calcium-dependent release of endogenous glutamate from these preparations. Both Potassium and kainic acid enhanced the release of glutamate from guinea-pig purified cerebrocortical synaptosomes. CLAD inhibited this release in a manner sensitive to the A₁-adenosine receptor antagonist 8-cyclopentyl-theophylline (CPT). CLAD reduced calcium entry into rat cortical synaptosomes loaded with the calcium indicator quin-2. This effect was reversed by theophylline. Kainic acid failed to enhance calcium influx in the same preparation. Purified cortical synaptosomes preloaded with quin-2, were exposed to barium ions in a calcium-free medium. Barium influx caused a rapid increase influorescence which was inhibited by CLAD. The selective A1 agonist cyclopentyladenosine was not as effective while the A2 agonist cyclopropyl-carboxamidoadenosine was ineffective.

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