Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease.

Substitutive therapy using fetal striatal grafts in animal models of Huntington disease (HD) have already demonstrated obvious beneficial effects on motor indices. Using a new phenotypic model of HD recently designed in primates, we demonstrate here complete and persistent recovery in a frontal-type cognitive task two to five months after intrastriatal allografting. The striatal allografts also reduce the occurrence of dystonia, a major abnormal movement associated with HD. These results show the capacity of fetal neurons to provide a renewed substrate for both cognitive and motor systems in the lesioned adult brain. They also support the use of neural transplantation as a potential therapy for HD.

Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease.

Huntington's disease (HD) is an inherited disorder characterized by cognitive impairments, motor deficits, and progressive dementia. These symptoms result from progressive neurodegenerative changes mainly affecting the neostriatum. This pathology is fatal in 10 to 20 years and there is currently no treatment for HD. Early in the course of the disease, initial clinical manifestations are due to striatal neuronal dysfunction, which is later followed by massive neuronal death. A major therapeutic objective is therefore to reverse striatal dysfunction prior to cell death. Using a primate model reproducing the clinical features and the progressive neuronal degeneration typical of HD, we tested the therapeutic effects of direct intrastriatal infusion of ciliary neurotrophic factor (CNTF). To achieve a continuous delivery of CNTF over the full period of evaluation, we took advantage of the macroencapsulation technique. Baby hamster kidney (BHK) cells previously engineered to produce human CNTF were encapsulated into semipermeable membranes and implanted bilaterally into striata. We show here that intracerebral delivery of low doses of CNTF at the onset of symptoms not only protects neurons from degeneration but also restores neostriatal functions. CNTF-treated primates recovered, in particular, cognitive and motor functions dependent on the anatomofunctional integrity of frontostriatal pathways that were distinctively altered in this HD model. These results support the hypothesis that CNTF infusion into the striatum of HD patients not only could block the degeneration of neurons but also alleviated motor and cognitive symptoms associated with persistent neuronal dysfunction.

Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies.

Chronic systemic treatment with 3-nitropropionic acid in rats produces persistent dystonia and bradykinesia, and striatal lesions reminiscent of Huntington's disease. However, the interpretation of results obtained with this model are complicated by a heterogeneous distribution of the response to a given toxic dose of 3-nitropropionic acid: approximately half of the animals develop selective striatal lesions, which in certain cases are associated with extrastriatal lesions, and the other half are apparently spared. Thus, the chronic 3-nitropropionic acid lesion model can be difficult for neuroprotection studies in which a consistent response to neurotoxic treatment is prerequisite. We hypothesized that some of the variability in the model was related to the use of Sprague-Dawley rats, since inter-individual variability in response to various stressful conditions has been described previously in this rat strain. We therefore compared 3-nitropropionic acid toxicity in rat strains known to be highly (Fisher 344) or poorly (Lewis) responsive to stress and compared the distribution of responses to that of Sprague-Dawley rats. In a protocol of intraperitoneal injection, toxicity of 3-nitropropionic acid was highest in Fisher rats, intermediate in Sprague-Dawley rats and lowest in Lewis rats. In addition, survival curves showed a more heterogeneous response to 3-nitropropionic acid toxicity in Sprague-Dawley rats than that observed in Lewis and Fisher rats. These differences between Sprague-Dawley and Lewis rats were confirmed in a protocol of subcutaneous 3-nitropropionic acid intoxication using osmotic minipumps, where doses up to 36-45mg/kg per day for five days were necessary to induce striatal lesions in Lewis rats as compared to 12-14mg/kg per day for five days in Sprague-Dawley rats. The selectivity of the striatum to lesions, and homogeneous progression of symptoms and neurodegeneration, were more consistently observed in Lewis as compared to Sprague-Dawley rats. These results suggest that vulnerability to 3-nitropropionic acid may depend on genetic factors, which could also influence the physiological response to stress. The present findings also establish an improved model of progressive striatal degeneration in the rat adapted for the testing of new neuroprotective strategies.

Serial 1H-NMR spectroscopy study of metabolic impairment in primates chronically treated with the succinate dehydrogenase inhibitor 3-nitropropionic acid.

Previous studies in primates have shown that chronic systemic administration of the succinate dehydrogenase (SDH) inhibitor, 3-nitropropionic acid (3NP), replicates most of the motor, cognitive, and histopathological features of Huntington's disease. In the present study, serial 1H-NMR spectroscopy (1H-MRS) assessment of striatal and occipital cortex concentrations of N-acetylaspartate, phosphocreatine/creatine, choline, and lactate, were obtained every 2-weeks during the entire course of a chronic 3NP treatment in baboons. A region-selective increase in lactate was detected in the striatum of the 3NP-treated animals, either immediately before or in conjunction with a lesion in the dorsolateral putamen detected by T2-MR imaging. Absolute 1H-MRS quantitation demonstrated a progressive and region-specific decrease in striatal N-acetylaspartate, creatine, and choline, occuring as early as 3 weeks before the first detection of lactate. These results demonstrate that 1H-MRS can be used to monitor early stages of brain metabolic impairment. In addition, given that 3NP-induced SDH inhibition following systemic injection similarly affects all brain regions, the striatal selective decreases in N-acetylaspartate or creatine concentrations are not simply related to the level of mitochondrial impairment but to a preferential vulnerability of the striatum to 3NP-induced toxicity.

Partial inhibition of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat.

Chronic inhibition of succinate dehydrogenase (SDH) by systemic injection of the selective inhibitor 3-nitropropionic acid (3NP) has been used as an animal model for Huntington's disease (HD). However, the mechanisms by which 3NP produces lesions in the striatum are not fully characterized. A quantitative histochemical method was developed to study the level of regional SDH inhibition resulting from intraperitoneal injection of 3NP or chronic intoxication using osmotic pumps. The results showed that (a) 3NP was an irreversible SDH inhibitor in vivo, (b) the level of SDH inhibition in the striatum (the brain region most vulnerable to 3NP) was similar to that observed in other brain regions not affected by the toxin, such as the cerebral cortex, and (c) the neurotoxic threshold of SDH inhibition in the brain was 50-60% of control levels. The present study demonstrates that the selective degeneration in the striatum observed after chronic 3NP administration cannot be ascribed to a preferential inhibition of SDH in this particular brain region. This work also suggests that the partial decrease in the activity of the respiratory chain complex II-III reported in HD patients may be sufficient to induce the selective striatal degeneration observed in this disorder.