Insulin attenuates ischemic brain damage independent of its hypoglycemic effect.

Insulin, an endogenously produced circulating peptide that enters the brain, has been shown to reduce ischemic brain and spinal cord damage in several animal models. Because of its potential clinical use in humans, the present study was undertaken to test the hypotheses that (a) survival and regional ischemic brain necrosis are improved by insulin; (b) insulin requires concomitant hypoglycemia to exert its neuroprotective effect; (c) insulin is still neuroprotective with delayed administration after an episode of postischemic hypotension; and (d) insulin is beneficial after normoglycemic, as well as hyperglycemic ischemia. Rats were subjected to 10.5 min two-vessel occlusion forebrain ischemia followed by 30 min of hypotension to increase the infarction rate. Insulin administered concomitantly with glucose significantly reduced the seizure rate, as well as cortical and striatal neuronal necrosis below that seen in untreated animals. Neuroprotection was seen whether insulin was given before or after a 30-min episode of postischemic hypotension. Insulin reduced pan-necrosis in addition to selective neuronal necrosis: The infarction rate was reduced in the cerebral cortex, thalamus, and substantia nigra pars reticulata. Normoglycemic ischemia produced only selective neuronal necrosis, but a beneficial effect on structural damage was also seen. The results indicate that insulin acts directly on the brain, independent of hypoglycemia, to reduce ischemic brain necrosis. Possible direct CNS mechanisms of action include an effect on central insulin receptors mediating inhibitory neuromodulation, an effect on central neurotransmitters, or a growth factor effect of insulin.

Postischemic seizures and necrotizing ischemic brain damage: neuroprotective effect of postischemic diazepam and insulin.

Insulin has recently been shown experimentally to modify ischemic brain damage when administered either before or after the episode of ischemia. In controlled studies in the rat, high doses of insulin (greater than or equal to 8 IU/kg) result in seizures and early death. The present study was undertaken to determine whether diazepam, a potent, centrally penetrating GABAmimetic, alone or in combination with insulin, could mitigate postischemic seizures or regional selective neuronal necrosis and infarction. Forebrain ischemia was induced in rats for 10 1/2 minutes by carotid clamping and hypotension. The animals were observed clinically until elective perfusion-fixation and quantitative pathologic examination at 1-week recovery. Diazepam, either alone or with insulin, reduced regional brain necrosis and reduced the seizure rate. Insulin alone also led to reduced regional necrosis. However, the combination of diazepam plus insulin yielded the greatest proportion of undamaged brains in the hippocampus, thalamus, and midbrain. In the neocortex, the diazepam-only group showed the greatest number of normal hemispheres. Hypothalamic infarction was eliminated by all three treatments. Seizures per se were associated with increased damage in the cerebral cortex, thalamus, and brainstem, irrespective of treatment group. The findings indicate that ischemic brain necrosis can be mitigated by diazepam and insulin treatment begun in the immediate postischemic period.

Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats.

We investigated the ability of postischemic insulin administration to modify the structural and neurobehavioral consequences of cerebral ischemia in rats. Forebrain ischemia was induced in fed rats by combining controlled systemic hypotension with bilateral carotid artery clamping for 10 1/2 minutes. Following clamp release, one group of six rats [corrected] was given insulin (2 IU/kg s.c. b.i.d.) for 1 week. An ischemic-control group of five rats [corrected] received no postischemic treatment. A sham-ischemia group of rats was used as a behavioral control. Throughout the recovery period until sacrifice, the drinking water of all rats was supplemented with 25% glucose. Rats were trained on two water maze place navigation tasks 1-2 months after ischemia. Escape latencies and swim patterns were recorded. Performance in the insulin-treated group was better than that in the ischemic-control group (p less than 0.05) on both tasks and did not differ significantly from that of the sham-ischemia group. Improvement in behavior correlated with a significant reduction in CA1 hippocampal necrosis in the insulin-treated group (p less than 0.05). Our findings demonstrate that postischemic treatment with insulin improves neurobehavioral performance in addition to lessening ischemic neuronal necrosis.

Platelet aggregability in sleep-related stroke.

We examined platelet aggregability during nocturnal sleep and daytime wakefulness in patients with a history of sleep-related stroke onset (SOS) and compared it to that of matched awake-onset stroke (AOS) patients and controls without evidence of vascular disease. Aggregability was evaluated in-vitro at least seven weeks following stroke onset. Platelets were more aggregable to ADP, collagen and arachidonic acid (AA) during both sleep and wakefulness in patients with AOS (p less than 0.01). No significant difference in the mean aggregation thresholds during sleeping or waking periods were found between SOS and control groups. However, platelets were significantly more responsive to AA during sleep than during wakefulness in the SOS patients (p less than 0.01). This difference was confined to the subgroup of SOS patients who had experienced nocturnal as opposed to daytime sleep-related stroke onset, suggesting that the observed difference in platelet responsiveness to AA may be related to a circadian fluctuation in platelet aggregability rather than to a sleep-related fluctuation. Significant sleep-related changes in platelet aggregability were not identified in the other two groups.

The effect of postischemic blood glucose levels on ischemic brain damage in the rat.

The effect of insulin-induced hypoglycemia following 10.5 minutes of forebrain ischemia was studied in the rat. All groups received preischemic glucose loading (2 gm/kg) to promote brain infarction. Following completion of ischemia, rats received either 2 to 3 IU/kg (low-dose group) or 8 to 20 IU/kg (high-dose group) insulin. During the survival period, blood glucose concentrations were maintained in the ranges of 1.2 to 2.9 mM and 2.9 to 4.9 mM, respectively, for the low-dose and high-dose insulin groups. Control rats were given 2 gm/kg glucose immediately following ischemia. During the recovery period, until perfusion at 7 days, they were given glucose, 2 gm/kg, twice daily by intraperitoneal injection, and their drinking water was supplemented with 25% glucose. Mortality (p less than 0.05) and postischemic seizure incidence (p less than 0.01) were significantly reduced in the low-dose insulin group compared to the control group. Mortality was increased in the high-dose insulin group compared to the control group and was associated with an increased incidence of postischemic seizures. Neuropathological examination revealed no cortical infarction in the low-dose or high-dose insulin-treated rats compared to a 60% incidence of cortical infarction in the control group. In addition, the high-dose insulin-treated group showed a significant reduction in striatal and hippocampal CA1 selective neuronal necrosis compared to control rats with comparable survivals (p less than 0.05). The findings suggest that postischemic blood glucose concentrations play an important role in modulating both ischemic infarction and selective neuronal necrosis.

Internal ophthalmoplegia and cranial neuropathy without external ophthalmoplegia. A report of 2 cases.

Two patients presented with an acute syndrome of internal ophthalmoplegia in the absence of external ophthalmoplegia, bilateral involvement of other cranial nerves, and minimal evidence of peripheral neuropathy. Cerebrospinal fluid protein was slightly raised, and moderate slowing of nerve conduction velocity was observed peripherally. It is suggested that these cases may represent a variant of acute post-infectious polyneuritis.

The value of noninvasive investigation in the diagnosis of total occlusion of the internal carotid artery.

A battery of simple noninvasive tests consisting of directional Doppler ultrasound and carotid phonoangiography has been used to detect carotid stenosis in 700 patients Forty four carotid occlusions in 42 patients were confirmed on angiography, and this study examines the accuracy of this noninvasive battery in predicting the presence of an occluded internal carotid artery. Although the sensitivity of the battery described has been 70% for occlusion, with a specificity of 98% (only five false positives), this relatively low sensitivity and the uniform requirement for surgery in the false positive group have led us to conclude that this battery should not be used as a substitute for angiography when the diagnosis of internal carotid occlusion requires to be confirmed. Nevertheless, these noninvasive tests do have a role in alerting the physician to the presence of carotid occlusion and contralateral carotid artery stenosis, allowing more specific planning of any subsequent arteriography required.

Internal carotid artery occlusion: clinical and therapeutic implications.

Five hundred patients referred to the Cerebrovascular Clinic of the Johannesburg Hospital were examined by a battery of noninvasive tests and angiography. Thirty four occlusions of the internal carotid artery were found in 32 patients. These patients were prospectively evaluated, including clinical examination, analysis of risk factors and subsequent management. This group of patients was followed up for a mean period of 18 months, and the clinical and laboratory findings and follow up data of this group were compared to an age and sex matched group of patients with matched presenting symptoms, but with patent internal carotid arteries on angiography. Four clinical patterns emerged in the patients with occluded carotid arteries; asymptomatic (3), TIA's (17), initial fixed stroke (7), and TIA with subsequent stroke (5). Follow up of the occluded group revealed 19 patients (59%) with no further symptoms and no indication for surgical intervention. Nine patients required surgery; 4 external carotid endarterectomies (ipsilateral), 4 internal carotid endarterectomies (contralateral), and one extracranial to intracranial bypass. Two were lost to follow up and one died. After 18 months mean follow up 29 patients (91%) were well and asymptomatic. Follow up for a similar period of the non-occluded group revealed three deaths, three late strokes and three myocardial infarctions. None were lost to follow up. After 19 months mean follow up 26 patients (81%) were well with no new neurological symptoms. The prognosis of appropriately treated patients with total occlusion of the internal carotid artery does not appear to be worse than in patients with similar presenting features and patent carotid arteries.(ABSTRACT TRUNCATED AT 250 WORDS)