Exacerbation of blood-brain barrier breakdown, edema formation, nitric oxide synthase upregulation and brain pathology after heat stroke in diabetic and hypertensive rats. Potential neuroprotection with cerebrolysin treatment.

Abstract

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38°C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50mg/kg, i.p./day for 3days) treatment. After 6weeks, DBHY rats show 20-30mM/L Blood Glucose and hypertension (180-200mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.