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.