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 ganglia. Post insult administration of insulin-like growth factor-1 is neuroprotective, particularly in the striatum. Insulin-like growth factor-1 is also known to be a neuromodulator of several types of striatal neurons. The striatum comprises various phenotypic neurons with a complex neurochemical anatomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal neurons. Bilateral brain injury was induced in near term fetal sheep by 30 min of reversible carotid artery occlusion. A single dose of 3 microg of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min following ischemia. The histological and immunohistochemical outcome were examined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the percentage of neuronal loss in the striatum compared with the vehicle treated group (n = 10, 28.3+/-5.1% vs 55.5+/-17.3%, P < 0.005). Immunohistochemical studies showed that ischemia resulted in a significant loss of calbindin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxylase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neurons, compared with sham controls. Insulin-like growth factor-1 markedly prevented the loss of calbindin-28kd (n = 7, P < 0.05), choline acetyltransferase (n = 7, P < 0.05), neuropeptide Y (n = 7, P < 0.05), neuronal nitric oxide synthase (n = 8, P < 0.05) and glutamate acid decarboxylase (n = 9, P < 0.05) immunopositive neurons, but failed to protect parvalbumin (n = 6) immunopositive neurons. The present study indicates that the therapeutic effect of insulin-like growth factor-1 in the basal ganglia is selectively associated with cholinergic and some phenotypic GABAergic neurons. These data suggest a potential role for insulin-like growth factor-1 in preventing cerebral palsy due to perinatal asphyxia.
Guan
J
J
Research Center for Developmental Medicine and Biology, School of Medicine, University of Auckland, New Zealand. j.guan@auckland.ac.nz
Bennet
T L
TL
George
S
S
Waldvogel
H J
HJ
Faull
R L
RL
Gluckman
P D
PD
Keunen
H
H
Gunn
A J
AJ
D000818:Animals; D002545:Brain Ischemia / Q000196:embryology* / Q000473:pathology; D064026:Calbindins; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000196:embryology* / Q000473:pathology; D005333:Fetus / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012756:Sheep / Q000196:embryology
D064026:Calbindins; D009478:Neuropeptide Y; D018696:Neuroprotective Agents; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D007334:Insulin-Like Growth Factor I; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase