Pig xenografts to the immunocompetent rat brain: Survival rates using distinct neurotoxic lesions in the nigrostriatal pathway and two rat strains.

Porcine foetal neurons for xenotransplantation in Parkinson's disease (PD) is an alternative source to human fetuses. One of the obstacles facing brain xenotransplantation is the existence of an immune response, which prevents long-term graft survival. Experimental results concerning the survival time of porcine foetal neurons implanted into the brain of immunocompetent rats have been quite different from one study to another, suggesting an effect on graft survival of uncontrolled experimental parameters. To identify such parameters, we have first analyzed the survival of porcine foetal nigral neurons at 5 and 10 weeks after implantation into the striatum of immunocompetent rats having different types of brain lesion affecting cells (quinolinic acid) or projections to the striatum (MPP+, 6-OHDA). In a second experiment, graft survival was analyzed in two strains of recipient rats (female Sprague-Dawley and male Lewis rats) in conditions of ipsilateral dopaminergic denervation using 6-OHDA. The characteristics of surviving grafts were assessed by measuring the graft volume, the number of TH+ neurons, the size of TH+ neurons soma, and CD5+ cell infiltration. Long-term survival (> or = 10 weeks) of porcine neurons could be observed in all experimental models. However, there was no significant difference in graft survival rates and characteristics of the surviving grafts between the lesioned groups, or between Sprague-Dawley and Lewis rats. Altogether, results were highly variable within groups of grafts exposed to similar experimental procedures at both 5 and 10 weeks post-grafting. We conclude that the distinct neurotoxins and host rat strains used in our experimental design are not major factors influencing the rejection time-course of primary neural xenografts.

Effects of early visual experience and diurnal rhythms on BDNF mRNA and protein levels in the visual system, hippocampus, and cerebellum.

The expression of brain-derived neurotrophic factor (BDNF) mRNA and the secretion of BDNF protein are tightly regulated by neuronal activity. Thus, BDNF has been proposed as a mediator of activity-dependent neural plasticity. Previous studies showed that dark rearing (DR) reduces BDNF mRNA levels in the primary visual cortex (V1), but the effects of visual experience on BDNF protein levels are unknown. We report that rearing in constant light or DR alters BDNF mRNA and protein levels in the retina, superior colliculus (SC), V1, hippocampus (HIPP), and cerebellum (CBL), although the changes in mRNA and protein are not always correlated. Most notably, DR increases BDNF protein levels in V1 although BDNF mRNA is decreased. BDNF protein levels also undergo diurnal changes. In the retina, V1, and SC, BDNF protein levels are higher during the light phase of the circadian cycle than during the dark phase. By contrast, in HIPP and CBL, the tissue concentration of BDNF protein is higher during the dark phase. The discrepancies between the experience-dependent changes in BDNF mRNA and protein suggest that via its effects on neuronal activity, early sensory experience alters the trafficking, as well as the synthesis, of BDNF protein. The circadian changes in BDNF protein suggest that BDNF could cause the diurnal modulation of synaptic efficacy in some neural circuits. The fluctuations in BDNF levels in nonvisual structures suggest a potential role of BDNF in mediating plasticity induced by hormones or motor activity.

A partial agonist model used in the allosteric modulation of the NMDA receptor.

We used a partial agonist model to understand further the allosteric modulation of D,L-(E)-2-amino4-propyl-5-phosphono-3-pentenoic acid ([3H]CGP-39653) binding by glycine, 1-hydroxy-3-amino-2-pyrrolidone (HA-966) and 5,7-dichlorokynurenic acid at the NMDA receptor. Binding of [3H]CGP-39653 was investigated in homogenates of cortex, hippocampus and cerebellum of adult rat. Glycine, HA-966 and 5,7-dichlorokynurenic acid maximally decreased the binding of 10 nM of [3H]CGP-39653 by approximately 50, 40 and 22%, respectively. Glycine, HA-966 and 5,7-dichlorokynurenic acid reduced [3H]CGP-39653 binding with IC50 values of 0.31, 11 and 0.044 microM, respectively. The decrease in [3H]CGP-39653 binding was due to a reduced affinity (Kd) and number of binding sites (Bmax) by all three drugs at concentrations where approximately maximum inhibition was observed. Glycine, HA-966 and 5,7-dichlorokynurenic acid lowered the Bmax by approximately 29, 16 and 10%, respectively, whereas the Kd values were increased by approximately 84, 44 and 32%, respectively, in cortex and hippocampus. There was no change in the binding of [3H]CGP-39653 in the cerebellum. The model used revealed that neither 5,7-dichlorokynurenic acid nor HA-966 had partial agonist characteristics in respect with the allosteric modulation of [3H]CGP-39653 binding. Furthermore, the results showed that brain regions have different pharmacological profiles which may depend on the NMDA receptor subunit composition.