Microinjections of kainic acid (KA) into the striatum of experimental animals result in degeneration of local intrinsic as well as efferent neurons, leaving axons and terminals of extrinsic neurons intact. The resulting biochemical and histological picture appears strikingly analogous to that described in the striatum of patients with Huntington's disease (HD). However, a novel excitotoxin, quinolinic acid (QA) has recently been reported to be a more accurate biochemical model of HD. The behavioral consequences and the effects on ChAT, GAD, TH, substance P and somatostatin of QA lesions of the rat striatum will be determined and compared to those produced by KA. Transplantation of day 17 rat fetal striatal ridge tissue into KA lesioned rat striatum produces a time dependent amelioration of the nocturnal hyperactivity observed in KA lesioned rats. The long-term survival of transplanted tissue and the effect of animal sex on the survival of transplanted tissue will be assessed as these variables have potential clinical significance. The optimal time, following neuronal injury with KA or QA, in which transplanted material survives, grows and ameliorates locomotor abnormalities will be investigated in the animal model. The use of human fetal tissue transplants into human patients may encounter ethical or logistical problems. The use of non-human donor tissue might be a possible alternative. The feasibility of cross-species transplants from fetal guinea pig, mouse and cat will be explored using the immune suppressant drug cyclosporin A in host rats. These rats will be tested for any reversal of abnormal locomotor activity to determine functional integration of donor and host tissue. The short-term survival of transplanted tissue from these other species will be determined by histological analysis. Interestingly, the injection of fetal rat striatal tissue into intact adult rat striatum produces """"""""lesion-like"""""""" increases in locomotor activity. It is proposed to further investigate the specificity of this phenomenon. These studies should help elucidate the conditions for optimal use of the transplantation technique in a rat model of HD and expedite the investigation of the therapeutic potential of the transplant technique in human HD patients.
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