Nerve terminal damage in cerebral ischemia: protective effect of alpha-methyl-para-tyrosine.

Abstract

SUMMARY Mongolian gerbils were treated with alpha-methyl-para-tyrosine methyl ester (AMPT, a tyrosine hydroxylase inhibitor), in order to decrease brain levels of catecholamines. Six hours later, unilateral ischemic stroke was induced by ligation of the left common carotid artery. The delayed degeneration of nerve terminals was studied sixteen hours later by measuring the high-affinity uptake of radiolabeled transmitters by isolated synaptosomes. Dopamine, serotonin and glutamate terminals were studied. AMPT-treated gerbils were compared to untreated (no AMPT) animals; 220 gerbils were studied. AMPT pretreatment (100, 250 and 400 mg/kg) produced a dose-dependent protection of all three types of nerve terminals. In the absence of AMPT pretreatment, the uptake of radiolabeled transmitters by the ischemic hemisphere, expressed as a percentage of that seen in the contralateral (unaffected) side of the brain, was as follows (mean ± SEM): 27.3 ± 5.2% for dopamine terminals, 49.5 ± 6.2% for serotonin terminals, and 42.7 ± 5.3% for glutamate terminals. Protection was essentially complete at a dose of 400 mg AMPT per kg. The number of animals with significant damage to nerve terminals was reduced from 38.5% in untreated animals to 11.1% in animals treated with AMPT 400 mg/kg. Although the nerve terminals were protected, gerbils still showed the behavioral signs of unilateral stroke due to the permanent occlusion of the left carotid. These results indicate that endogenous dopamine may play a significant role in ischemic damage to nerve terminals in the cerebrum. Stroke Vol 16, No 5, 1985 THE MEASUREMENT of high affinity uptake of radiolabeled neurotransmitters by isolated synaptosomes can be used to evaluate damage to nerve terminals in experimental animals with cerebral ischemia. The uptake and accumulation of neurotransmitter against a concentration gradient is a complex neuronal function that requires energy and the structural integrity of the axonal membrane. The neuronal cell type is specified by the high-affinity binding of neurotransmitter to the axonal transport system. Prior studies have determined that the catecholamine nerve terminals that take up dopamine (DA) and norepinephrine (NE) are damaged to a significantly greater degree by cerebral ischemia than terminals incorporating serotonin (5-HT), GABA or glutamate. 1 -2 All nerve terminals were able to function normally in vitro when synaptosomes were isolated for up to eight hours after carotid ligation.1 However, by sixteen hours, severe reduction in uptake had occurred. Since the potassium-stimulated release of radiolabeled transmitter proceeded normally, the reduction in uptake appeared to be due to loss of terminals, rather than to reduced uptake in existing terminals. This reduction in uptake probably represents irreversible damage to the nerve terminals because function cannot be restored by incubation in vitro with adequate supplies of substrate and oxygen. Measurement of the levels of transmitters in the ischemic hemisphere of gerbils with irreversi...

Prolonged Opportunity for Ischemic Neuroprotection with Selective κ-Opioid Receptor Agonist in Rats

“…[12][13][14][15] For example, depletion of catecholamine stores by ␣-methyl-para-tyrosine or by surgically lesioning the nigrostriatal tract, protects intrinsic striatal neurons from injury following global cerebral ischemia. 15 While the precise mechanism of neuronal injury by DA is unclear, byproducts of its metabolism such as hydrogen peroxide, superoxide ion, and oxygen radicals have been implicated in this deleterious process. 23 In our study, there was an expected acute large increase in DA in the first 40 minutes microdialysis samples following the onset of MCAO.…”

“…12,13 For example, previous studies have demonstrated a greater susceptibility of dopaminergic nerve terminals to ischemic injury. [13][14][15] Amelioration of histopathological injury following cerebral ischemia has been demonstrated following attenuation of ischemia-induced surges in extracellular dopamine (DA) with pharmacological agents 12,16 as well as surgically by nigrostriatal lesioning. 17 In the present study, we sought to determine the "therapeutic window" for ischemic neuroprotection with the highly selective KOR agonist, BRL 52537 hydrochloride ((Ϯ)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine), 18,19 in a well-characterized model of transient focal ischemia with MCAO in rats.…”

Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections.

“…However, accumulating evidence suggests that endogenous DA may act as a neurotoxin and thereby participate in the pathophysiology of the disease. For example, DA appears to be involved in the striatal neuropathology associated with several conditions, including ischemia (1,2), exposure of the area to high levels of excitatory amino acids (3, 4), and systemic methamphetamine treatment (5,6). Evidence for the involvement of DA in this neuropathology derives from the observation that, in each case, toxicity was attenuated by pharmacologically or surgically reducing striatal DA availability prior to the insult.…”

Sequelae of Hypoxia and Ventilation

“…Data suggest that depletion of DA by alpha methylparatyrosine may protect neurons against hypoxic stress and injury. 4,5 Similarly, DA blockade can be used to reduce hypoxic damage in the hippocampus. 6 DA-2 antagonist agents also enhance acetylcholinesterase release, which may be an additional mechanism that assists in alleviating the symptoms of delirium.…”