Rodent Studies

Infusions of trophic factors such as NGF or implants of cells genetically modified to secrete NGF have proven effective in preventing the neuropathological sequelae resulting from intrastriatal injections of excitotoxins, including QA (92-95). Emerich and colleagues (96,97) examined the ability of encapsulated trophic factor-secreting cells to affect central striatal

Figure 8 Cognitive function in young, middle-age, and aged rats following implantation of encapsulated NGF-producing cells into the lateral ventricles. (a) Prior to implantation, animals were divided into the 50% worse and 50% better performers in a water maze task. (b) Following implantation, NGF was found to improve performance in the middle-age and aged animals. Moreover, the improvements in cognitive performance were greatest in those animals that demonstrated the worst initial performance [see (67) for additional details].

Figure 8 Cognitive function in young, middle-age, and aged rats following implantation of encapsulated NGF-producing cells into the lateral ventricles. (a) Prior to implantation, animals were divided into the 50% worse and 50% better performers in a water maze task. (b) Following implantation, NGF was found to improve performance in the middle-age and aged animals. Moreover, the improvements in cognitive performance were greatest in those animals that demonstrated the worst initial performance [see (67) for additional details].

neurons in a series of defined animal models of HD. In these experiments, rats received implants of NGF- or CNTF-pro-ducing cells into the lateral ventricles (Fig. 10). One week later, the same animals received unilateral injections of QA (225 nmol) or the saline vehicle into the ipsilateral striatum.

An analysis of Nissl-stained sections demonstrated that the size of the lesion was significantly reduced in those animals receiving NGF and CNTF cells, compared with those animals receiving control implants. Moreover, both NGF and CNTF cells attenuated the extent of host neural damage produced by

Figure 9 Photomicrographs through the septal diagonal band complex of cynomolgus monkeys. Monkeys received a fornix transection together with polymer-encapsulated implants of either BHK-control cells (A) or a BHK-NGF cells (B). Note the extensive loss of NGF receptor positive neurons ipsilateral to the lesion (right) in the control-implanted monkeys. In contrast, numerous NGF cholinergic neurons were observed in fornix-transected monkeys receiving the BHK-NGF implant. High-power photomicrographs illustrating the morphology of cholinergic neurons within the medial septum of young monkeys receiving BHK-NGF (C-E) implants. Note the enlarged perikarya and extensive neuritic arbor displayed by monkeys receiving the BHK-NGF implants [see (69) for additional details].

Figure 9 Photomicrographs through the septal diagonal band complex of cynomolgus monkeys. Monkeys received a fornix transection together with polymer-encapsulated implants of either BHK-control cells (A) or a BHK-NGF cells (B). Note the extensive loss of NGF receptor positive neurons ipsilateral to the lesion (right) in the control-implanted monkeys. In contrast, numerous NGF cholinergic neurons were observed in fornix-transected monkeys receiving the BHK-NGF implant. High-power photomicrographs illustrating the morphology of cholinergic neurons within the medial septum of young monkeys receiving BHK-NGF (C-E) implants. Note the enlarged perikarya and extensive neuritic arbor displayed by monkeys receiving the BHK-NGF implants [see (69) for additional details].

QA as assessed by a sparing of specific populations of striatal cells, including cholinergic, diaphorase-positive, and GA-BAergic neurons (Fig. 11). Neurochemical analyses have confirmed the protection of multiple striatal cell populations using this strategy (Table 3). These results suggested that implantation of polymer-encapsulated trophic factor-releasing cells can protect neurons from excitotoxin damage. Importantly, behavioral studies offer additional and compelling evidence of neuronal protection that can be produced in animal models of HD (Table 3). Trophic factor-secreting cells have provided extensive behavioral protection as measured by tests that assess both gross and subtle movement abnormalities. Moreover, these same animals show improved performance on learning and memory tasks, indicating the anatomical protection afforded by trophic factors in this model is paralleled by a robust and relevant behavioral protection (98).

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