Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol.

Self Cite

114

Hyperglycemia exacerbates neurologic damage in clinical and experimental central nervous system ischemia. The purpose of our study was to determine if insulin administration before significantly alters neurologic deficit and survival after ischemia using a newly developed rat cerebral ischemia model. One hour before the onset of ischemia, 40 200-300 -g Sprague-Dawley rats received intraperitoneal injections of either 1 ml normal saline or 0.4, 0.5, or 0.6 units regular insulin in 1 ml normal saline. Rats were then intubated and ventilated with 1-1.5% halothane. The aortic arch was exposed, and snares were placed on the innominate, left carotid, and left subclavian arteries. A 20-minute occlusion was begun, and anesthesia was discontinued. Baseline plasma glucose concentration was similar (p=0.48, Student's t test) in both groups, but it subsequently was significantly lower in the 0.4 unit insulin-treated group up to 4 hours after occlusion (p<0.0035, Student's t test). Neurologic deficit was scored on a 50-point scale (0=normal, 50=severe deficit) 1, 4, 18, and 24 hours after occlusion. In the 0.4 unit insulin-treated group the neurologic deficit score was significantly lower than in the salinetreated group 1, 4, 18, and 24 hours after occlusion (p<0.005, Student's t test). Survival was significantly higher (p=0.001) in the 0.4 unit insulin-treated (1.7 unit/kg dose) group than in the saline-treated group. No rats died when preocclusion plasma glucose concentration was between 65 and 175 mg/dl. We conclude that insulin can be used to maintain plasma glucose concentration within a normoglycemic to mildly hypoglycemic range, which is associated with decreased behavioral neurologic deficit and increased survival following temporary cerebral ischemia. Hyperglycemia or more extreme hypoglycemia (glucose concentration less than approximately 65 mg/dl) is detrimental in this model. (Stroke 1988;19:1411-1419) H yperglycemia has been shown to exacerbate neurologic deficit in many experimental models of central nervous system (CNS) hypoxic-ischemic injury. -8 Clinical studies also indicate an adverse effect on outcome when CNS ischemia occurs in the setting of hyperglycemia. Diabetic patients experiencing a stroke have significantly worse outcomes than nondiabetic stroke patients. 9 Other studies have confirmed an increased mortality rate in acute stroke patients with fasting plasma glucose concentrations of >110 mg/dl. 10 These findings suggest that even relatively mild hyperglycemia, whether exogenously or endogenously induced, significantly worsens postischemic neurologic outcome. In the clinical setting, hyperglycemia resulting from exogenous glucose administration is potentially preventable but often inadvertently produced by administration of intravenous fluids. A more difficult problem arises in dealing with endogenous elevations of plasma glucose concentrations in patients at risk for ischemic neurologic injury. Examples include cardiac arrest patients and evolving stroke patients with concurrent hyperglycemia and...

Section: Discussionmentioning

confidence: 99%

Insulin administration protects neurologic function in cerebral ischemia in rats.

LeMay

Gehua

Zelenock

et al. 1988

Self Cite

114

“…17 Briefly, the rats were placed on a 29x30-cm screen (grid size 0.6x0.7 cm) that could be rotated from 0° (horizontal) to 90° (vertical). The animal was placed on the horizontal screen and the screen was then rotated into the vertical plane.…”

Section: Methodsmentioning

confidence: 99%

Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats.

Warner

Gionet

Todd

et al. 1992

Background and Purpose: Hyperglycemia is known to aggravate ischemic brain damage. This study sought to determine if preischemic insulin-induced normoglycemia would improve outcome in hyperglycemic rats.Methods: Normal rats and rats with 5-7 days of streptozotocin-induced diabetes were studied. Normal rats served as either fasted normoglycemic controls or dextrose-infused (hyperglycemic) controls. In the acutely diabetic rats either no insulin was given or insulin was given at 30 or 90 minutes before ischemia so as to induce preischemic normoglycemia. All rats underwent 10 minutes of forebrain ischemia. After 5 days of recovery, motor function and histological outcome were assessed.Results: Untreated diabetic rats and dextrose-infused control rats had greater hippocampal CA1 damage than normoglycemic control rats. In contrast, insulin-treated diabetic rats had less hippocampal CA1 damage than either untreated diabetic rats or dextrose-infused control rats. Injury in the two insulin-treated groups was not significantly different from that in the normoglycemic control group (all three groups had plasma glucose values of 120-150 mg/dl immediately prior to ischemia). Despite similar plasma glucose values (300-400 mg/dl), fewer postischemic seizures (0% versus 67%) were observed in the untreated diabetic group than in the dextrose-infused control group (/>< 0.001).Conclusions: Hyperglycemia caused by either dextrose infusion or streptozotocin-induced diabetes resulted in exacerbated ischemic brain damage. Insulin therapy to rapidly induce preischemic normoglycemia improved outcome from forebrain ischemia in the acutely diabetic rats. Glucose-infused hyperglycemic rats frequently exhibited postischemic generalized seizures while acutely diabetic rats did not. The latter results implicate some adaptive/protective mechanism associated with acute streptozotocin-induced diabetes that results in a decreased sensitivity to hyperglycemia-augmented ischemic brain damage. (Stroke 1992;23:1775-1781 KEY WORDS • cerebral ischemia • diabetes mellitus • hyperglycemia • rats

“…9 Briefly, the rats were placed on a 29x30 cm screen (grid size 0.6x0.7 cm) that could be rotated from 0° (horizontal) to 90° (vertical). The animal was placed on the screen when horizontal, and the screen was then rotated into the vertical plane.…”

Section: Methodsmentioning

confidence: 99%

Forebrain ischemia induces selective behavioral impairments associated with hippocampal injury in rats.

Gionet

Thomas

Warner

et al. 1991

Two groups of rats were tested on a variety of motor and cognitive tasks after either 10 minutes of two-vessel occlusion forebrain ischemia (n=8) or sham operative procedures (n=6). Histological injury was absent in the sham-operated group. In the ischemic group, hippocampal injury was restricted to field CA1, while damage in the neocortex and caudoputamen was sparse. Motor tests performed on postoperative days 18 and 28 revealed no significant differences between the ischemic and sham-operated groups. Retention performance of a radial maze discrimination task was impaired, with a significant but transient increase in both working and reference memory errors. Passive avoidance acquisition and retention were not significantly affected, although conclusions concerning the utility of this task must be reserved because of variability in the behavior of the sham-operated rats. Morris maze spatial navigation (place learning) and open-field activity were insensitive to treatment group. These functional results are consistent with the observed histological injury and what is known about hippocampal injury and behavior, and they provide further guidance for the development of neurological assays appropriate for discriminating outcome from forebrain ischemia in rats.