The adrenalectomized rat : a model for neurodegeneration

The hippocampus is a highly organized laminar structure known to be a focus of damage in several neurodegenerative conditions. This neural structure is a primary target for glucocorticoids and has been strongly implicated in cognitive processes such as learning and memory. Adrenal steroids have a great variety of effects on the hippocampus which can be paradoxical, over exposure to glucocorticoids can be deleterious, adrenal hormone withdrawal can also produce damaging effects in the hippocampus. The present project was designed to study neurodegeneration in the hippocampus after adrenalectomy and identify the mechanisms involved in it.

The effects of long-term adrenalectomy on the behavior in young adult rats were studied. Adrenalectomy produced impairment in spatial learning and exploratory behavior. These behavioral changes could be due to neuron loss in the hippocampus induced by adrenalectomy. Quantification of neurons in the hippocampus showed cell loss in the dentate gyrus and the CAI-CA4 field. To further characterize the mechanisms involved in neuron loss we performed electron microscopy in adrenalectomized rat brain. Ultrastructurally, apoptotic and different varieties of degenerating cells were noticed both in the granule and pyramidal cells.

The neuroendocrine and immune system are interconnected. Thus we looked at immune responses to see if the inflammatory processes are associated with neurodegeneration produced by long-term adrenalectomy. Results showed upregulation of major histocompatibility complex (MHC) class II, CD4 and EDI (activated microglial marker) in the dentate, CA4, and CA3 areas of adrenalectomized rat hippocampus. These observations suggest that it could be primarily the neurodegeneration process that triggers these immune responses.

We continued studies on adrenalectomized rats to investigate the alteration of insulin-like growth factor- I (IGF-I ) receptor to look for the involvement of growth factors in adrenalectomy-induced neurodegeneration in the hippocampus. IGF-I receptor and its mRNA levels were significantly lower in the hippocampus of adrenalectomized rats. It is possible that adrenalectomy produces apoptotic and other forms of death in the hippocampus due to unavailability of some trophic factors like IGF-I which is necessary for neuronal survival.

In conclusion, this thesis presents evidence that this model can be used extensively to study neurodegeneration in mammalian brain, specifically apoptosis and other variations of neuron death. The involvement of growth factors and immune mechanisms in adrenalectomy-induced cell death can be valuable for evaluating different drug responses in relation to neurodegeneration.