Selective neuroprotective effects with insulin-like growth factor-1 in phenotypic striatal neurons following ischemic brain injury in fetal sheep

Severe perinatal asphyxia can lead to injury and dysfunction of the basal g anglia. Post insult administration of insulinlike growth factor-1 is neurop rotective, particularly in the striatum. Insulin-like growth factor-1 is al so known to be a neuromodulator of several types of striatal neurons. The s triatum comprises various phenotypic neurons with a complex neurochemical a natomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal ne urons. Bilateral brain injury was induced in near term fetal sheep by 30 min of re versible carotid artery occlusion. A single dose of 3 mu g of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min. fol lowing ischemia. The histological and immunohistochemical outcome were exam ined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the p ercentage of neuronal loss in the striatum compared with the vehicle treate d group (n = 10, 28.3 +/- 5.1% vs 55.5 +/- 17.3%, P < 0.005). Immunohistoch emical studies showed that ischemia resulted in a significant loss of calbi ndin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxy lase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neur ons, compared with sham controls. Insulin-like growth factor-1 markedly pre vented the loss of calbindin-28kd (n = 7, P < 0.05), choline acetyltransfer ase (n = 7, P < 0.05), neuropeptide Y (n = 7, P < 0.05), neuronal nitric ox ide synthase (n = 8, P < 0.05) and glutamate acid decarboxylase (n = 9, P < 0.05) immunopositive neurons, but failed to protect parvalbumin (n = 6) im munopositive neurons. The present study indicates that the therapeutic effect of insulin-like gro wth factor-1 in the basal ganglia is selectively associated with cholinergi c and some phenotypic GABAergic neurons. These data suggest a potential rol e for insulin-like growth factor-1 in preventing cerebral palsy due to peri natal asphyxia. (C) 1999 Elsevier Science Ltd. Published by Elsevier Scienc e Ltd. All rights reserved.