APOPTOSIS IN SUBSTANTIA-NIGRA FOLLOWING DEVELOPMENTAL HYPOXIC-ISCHEMIC INJURY

We have previously observed that either hypoxic-ischemic or excitotoxi c striatal injury during development is associated with a reduction in the adult number of dopaminergic neurons in the substantia nigra. Thi s decrease occurs in the presence of preserved striatal dopaminergic m arkers and in the absence of direct nigral injury. We have also observ ed that natural cell death, with the morphology of apoptosis, occurs i n the substantia nigra, and that there is an induced apoptotic cell de ath event following early striatal excitotoxic injury. We now report t hat forebrain hypoxic-ischemic injury is also associated with an induc ed cell death event in the substantia nigra, with both morphological a nd histochemical features of apoptosis. Induced apoptotic cell death o ccurs in immunohistochemically defined dopaminergic neurons. While the mechanisms for this induced cell death are not yet known, in the case of the pars compacta it may be related to the loss of normal striatal target-derived developmental support. Since dopaminergic neurons are postmitotic at the time of the injury, we conclude that this induced c ell death is responsible for the diminished adult number of dopaminerg ic neurons. We also conclude that hypoxic-ischemic injury to the devel oping brain in general causes not only direct, necrotic injury to vuln erable regions, but also induced apoptotic death at remote sites. The significance of this finding is that apoptosis is a distinct death mec hanism, with unique regulatory pathways, which can potentially be modi fied by approaches different from those which might influence cell dea th in regions of direct injury. In view of the present finding that ap optosis can occur in the setting of hypoxic-ischemic injury, and our p revious work demonstrating its occurrence following excitotoxic injury , it seems likely that it may occur following other forms of injury to the immature brain in which excitotoxic injury plays a role, such as seizures, head trauma and hypoglycemia.