Implantation of undifferentiated and predifferentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington's disease

ABSTRACT: BACKGROUND: Cell therapy is a potential therapeutic approach for several neurodegenetative disease, including Huntington Disease (HD). To evaluate the putative efficacy of cell therapy in HD, most studies have used excitotoxic animal models with only a few studies having been conducted in genetic animal models. Genetically modified animals should provide a more accurate representation of human HD, as they emulate the genetic basis of its etiology. RESULTS: In this study, we aimed to assess the therapeutic potential of a human striatal neural stem cell line (STROC05) implanted in the R6/2 transgenic mouse model of HD. As DARPP-32 GABAergic output neurons are predominately lost in HD, STROC05 cells were also predifferentiated using purmorphamine, a hedgehog agonist, to yield a greater number of DARPP-32 cells. A bilateral injection of 4.5x105 cells of either undifferentiated or predifferentiated DARPP-32 cells, however, did not affect outcome compared to a vehicle control injection. Both survival and neuronal differentiation remained poor with a mean of only 161 and 81 cells surviving in the undifferentiated and differentiated conditions respectively. Only a few cells expressed the neuronal marker beta-III-tubulin. CONCLUSIONS: Although the rapid brain atrophy and short life-span of the R6/2 model constitute adverse conditions to detect potentially delayed treatment effects, significant technical hurdles, such as poor cell survival and differentiation, were also sub-optimal. Further consideration of these aspects is therefore needed in more enduring transgenic HD models to provide a definite assessment of this cell line's therapeutic relevance. However, a combination of treatments is likely needed to affect outcome in transgenic models of HD.     

Protective effect of transgenic expression of porcine heat shock protein 70 on hypothalamic ischemic and oxidative damage in a mouse model of heatstroke

Background  

Transgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70β gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke.     

Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response

Background  

The infantile form of neuronal ceroid lipofuscinosis (also known as infantile Batten disease) is caused by hereditary deficiency of a lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1), and is characterized by severe cortical degeneration with blindness and cognitive and motor dysfunction. The PPT1-deficient knockout mouse recapitulates the key features of the disorder, including seizures and death by 7–9 months of age. In the current study, we compared gene expression profiles of whole brain from PPT1 knockout and normal mice at 3, 5 and 8 months of age to identify temporal changes in molecular pathways implicated in disease pathogenesis.