Effect of an adenosine A₁ receptor agonist and a novel pyrimidoindole on membrane properties and neurotransmitter release in rat cortical and hippocampal neurons

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• 作者：Eschke ; D. ; Brand ; A. ; Scheibler ; P. ; Hess ; S. ; Eger ; K. ; Allgaier ; C. ; Nieber ; K.
• 关键词：Adenosine ; A₁ receptors ; Pyrimidodindole ; Hypoxia ; Transmitter release ; Cortex ; Hippocampus ; Rat
• 刊名：Neurochemistry International
• 出版年：2001
• 出版时间：April, 2001
• 年：2001
• 卷：38
• 期：5
• 页码：391-398
• 全文大小：260 K

文摘

Activation of adenosine A₁ receptors by endogenous adenosine plays a neuroprotective role under various pathophysiological conditions including hypoxia. Intracellular recordings were made in rat pyramidal cells of the somatosensory cortex. Hypoxia (5 min) induced a membrane depolarization and a decrease of input resistance. The A₁ receptor agonist N⁶-cyclopentyladenosine (CPA, 100 μM) reversibly inhibited the hypoxic depolarization. The inhibition was also present after blockade of the A_2A, A_2B and A₃ receptor subtypes by selective antagonists. CPA had no effect on the hypoxic decrease of input resistance. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a selective A₁ receptor antagonist, which did not alter hypoxic depolarization when given alone abolished the inhibitory effect of CPA. Neither CPA nor DPCPX influenced membrane potential or apparent input resistance under normoxic conditions. The novel pyrimidoindole (R)-9-(1-methylbenzyl)-2-(4′-pyridyl)-9H-pyrimido[4,5-b]indole-4-amine (APPPI, 1 and 10 μM) reversibly diminished hypoxic depolarization but had no significant effect on input resistance. The effect of APPPI at a concentration of 1 μM, but not at 10 μM, was blocked by DPCPX (0.1 μM). CPA (100 μM) inhibited [³H]-noradrenaline ([³H]-NA) release from rat hippocampal brain slices significantly only in the presence of rauwolscine (0.1 μM), an α₂-adrenoceptor antagonist. APPPI (1 and 10 μM) exhibited an inhibitory effect similar to that observed with CPA. The effects of both CPA and APPPI were antagonized by DPCPX (0.1 μM). The present data suggest that mainly presynaptic mechanisms prevent neurons from hypoxic changes by an inhibition of transmitter release. However, in contrast to CPA, APPPI exhibited additional effects, which require further investigation.