Monoamine neurotransmitters in the evolution of infarction in ischemic striatum: morphologic correlation.

Evolution of infarction following cerebral ischemia is a delayed process, with spongiform degeneration of the neuropil occurring 6 to 8 hours after onset of ischemia. The brains of gerbils with stroke following unilateral carotid artery ligation were examined for catecholamine-derived fluorescence (CADF) by the Falck-Hillarp technique to study the relationship of catecholamine (CA) metabolism with damage to the neuropil. CADF could still be identified in the striatum for up to 16 hours after stroke and there appeared to be spongiform degeneration of the neuropil in relation to accumulations of CADF at 7 and 16 hours after stroke. Pretreatment of gerbils with a-methyl-p-tyrosine 400 mg/kg 6 hours prior to carotid ligation depleted the striatum of CADF until 16 hours after stroke and appeared to reduce the spongiform degeneration of the neuropil, though it did not affect ischemic degeneration of neuronal cell bodies. The continued presence of CADF in the striatum for up to 16 hours after stroke supports the previously reported findings that CA nerve terminals are still functional for 8 hours after stroke and that CA metabolism continues even though levels of CA are reduced immediately after onset of ischemia due to carotid artery ligation.

Cerebral blood flow in the evolution of infarction following unilateral carotid artery occlusion in Mongolian gerbils.

Cerebral blood flow (CBF) was measured in gerbils 2, 4, 7, and 12 hours after unilateral irreversible carotid artery ligation to determine if the delayed ischemic damage to nerve terminals that occurs over 8 hours after stroke could be due to changes in CBF. [14C]butanol (4.5 mu Ci in 45 microliter 0.9% saline) was injected into the femoral vein, and cpm accumulating in the cerebrum and in a catheter inserted in the abdominal aorta were measured. CBF (ml/100 g/min, mean +/- SEM) in sham-operated control gerbils was 108.4 +/- 37.5 in the left hemisphere and 123.8 +/- 37.1 in the right. CBF in the ischemic left cerebrum was 41.0 +/- 7.7 at 2 hours (n = 7), 21.6 +/- 7.2 at 4 hours (n = 4), 26.2 +/- 4.6 at 7 hours (n = 7), and 9.7 +/- 3.1 at 12 hours (n = 6). CBF in the nonligated right hemisphere was 115.0 +/- 15.3 at 2 hours, 70.4 +/- 23.3 at 4 hours, 80.4 +/- 14.6 at 7 hours, and 50.9 +/- 20.1 at 12 hours. As expected, CBF was significantly reduced in the ischemic left cerebral hemisphere compared with the nonligated right cerebral hemisphere at each time, but CBF in the ischemic left cerebral hemisphere was also significantly lower at 12 hours than at 2 hours (p = 0.002) and at 7 hours (p = 0.014). CBF in the nonligated right cerebral hemisphere was also lower at 12 hours than at 2 hours (p = 0.02). No changes in PCO2 or blood pressure accounted for these differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct evidence of acute, massive striatal dopamine release in gerbils with unilateral strokes.

Dopamine release into the extracellular space was measured with in vivo electrochemical detection in the ipsilateral and contralateral striata in Mongolian gerbils that suffered a stroke after acute unilateral carotid artery ligations. A sevenfold increase in the dopamine signal occurred within 15 minutes of carotid ligation in the ischemic side, while the unlesioned side had no significant change. Increased extracellular levels of dopamine persisted throughout the 3-hour recording period. Pretreatment with alpha-methyl-p-tyrosine 6 hours prior to recording significantly attenuated the signal increase. This study is the first direct demonstration of the marked, continuous dopamine release that occurs during acute cerebral ischemia.

Metabolism of monoamine neurotransmitters in the evolution of infarction in ischemic striatum.

The time course of changes in monoamine metabolism in ischemic striatum was assessed by measurement of levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxy-indole-acetic acid (5-HIAA) 2, 4, 7 and 16 hours after irreversible unilateral carotid ligation in Mongolian gerbils with stroke. DA was reduced to 30% of the level in the contralateral non-ischemic striata by 2 hours after stroke, but DOPAC was significantly elevated (p less than 0.01) to 227%, while HVA remained equal to control. At 4 hours after stroke, DOPAC was 86% of the contralateral non-ischemic striata but HVA had risen to 130%. At 7 hours after stroke, DOPAC in the ischemic striata was 148% of control, while HVA remained at 133%. By 16 hours after stroke, DA, DOPAC and HVA were depleted from the ischemic striata, corresponding to the time course for irreversible damage to the neurotransmitter uptake function of nerve terminals. 5-HT levels in the ischemic striata were 30% of control at 2 hours, 46% at 4 hours, 30% at 7 hours and 21% at 16 hours, while 5-HIAA remained equal to control throughout the time course. These studies indicate that monoamine metabolism continues in ischemic striatum for up to 8 hours after the onset of stroke following irreversible unilateral carotid ligation in the Mongolian gerbil, but metabolism of DA is disrupted by 16 hours after stroke while metabolism of 5-HT continues.

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

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.

Nerve terminal damage in cerebral ischemia: greater susceptibility of catecholamine nerve terminals relative to serotonin nerve terminals.

The energy-dependent uptake of (3H)-dopamine (DA), (3H)-norepinephrine (NE) and (3H)-serotonin (5-HT) was measured in synaptosomes isolated from either the whole cerebral hemispheres or the striata of gerbils after cerebral ischemia. Ischemic stroke was induced in the Mongolian gerbil by left common carotid ligation. Uptake values in the affected hemisphere (expressed as a percent of the corresponding control hemisphere) were 32.6% for DA, 35.1% for NE, and 52.0% for 5-HT, 16 hours after stroke. The differential reduction in uptake of the catecholamines relative to 5-HT was significant (p less than 0.005). This differential persisted when measures were made on isolated striata from the ischemic and control hemispheres. In the latter measurements, uptake of DA was 20.7% of control and uptake of 5-HT was 44.7% of control. Uptake of both DA and NE were significantly reduced in animals exhibiting milder circling behavior, while uptake of 5-HT was not. There was no significant reduction of uptake in animals subjected to left common carotid ligation not exhibiting signs of stroke. These studies indicate a selective sensitivity of catecholamine nerve terminals to damage in ischemic stroke.