Discrete regions of the adult CNS, including the subventricular zone (SVZ), do retain the capacity for neurogenesis. These progenitor cells may represent a potential new source of cells for replacement therapies in neuroregenerative diseases. An understanding of the microenvironmental signals regulating neurogenesis in the adult brain would facilitate the development of such therapeutic approaches. A particularly strong expression of dopamine D(3) receptor mRNA occurs in the proliferative SVZ during prenatal and early postnatal ontogeny. Although its expression diminishes following development, a restricted D(3) receptor expression persists in this region through adulthood, coincident with continued proliferation in this region. Here, we demonstrate a two-fold induction of cell proliferation (BrdU incorporation) in the SVZ and rostral migratory stream of the adult Sprague-Dawley rat brain following intrasubventricular administration of the dopamine D(3) receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) for 2 weeks. The number of BrdU-positive cells was elevated ten-fold from very low baseline levels in the neighbouring neostriatum, another region known to express D(3) receptors. These striatal BrdU-positive cells appeared within 3 days following intracerebral infusion of 7-OH-DPAT and were distributed homogeneously throughout the striatum following systemic administration. This suggests that these cells originate from resident progenitor cells rather than the SVZ. Dopamine D(3) receptor activation may serve as a proneuronal differentiation signal as 60-70% of the new cells had neuronal markers following 7-OH-DPAT infusion. These results suggest that the dopamine D(3) receptor may be a good drug target for cell replacement strategies, particularly because of the fact that its expression is almost exclusively limited to the nervous system.

The presence of endogenous stem cell populations in the adult mammalian CNS suggests an innate potential for regeneration and represents a potential resource for neuroregenerative therapy aimed at the treatment of neurodegenerative disorders, such as Parkinson's disease. However, it is first necessary to examine the microenvironmental signals required to activate these innate reparative mechanisms. The small molecule neurotransmitter dopamine has been shown to regulate cell cycle in developing and adult brain, and the D 3 receptor is known to play an important role in dopaminergic development. Pharmacological activation of the dopamine D 3 receptor has been shown to trigger neurogenesis in the substantia nigra of the adult rat brain. Here, we examined the cell proliferative, neurogenic, and behavioral effects of the dopamine D 3 receptor agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) in a 6-hydroxydopamine model of Parkinson's disease. Consistent with previous findings, we observed a significant induction of cell proliferation in the substantia nigra pars compacta (SN C ) with a time-dependent adoption of a neuronal dopaminergic phenotype in many of these cells. Indices of nigrostriatal integrity were also affected. Dopaminergic cell counts in the lesioned SN C recovered substantially in a time-dependent manner. Similarly, retrograde tracing revealed a restoration of striatal innervation from these cells, with evidence for projections arising from newly generated cells. Finally, we observed a substantial and persistent recovery of locomotor function in these animals. The results of these studies will further our understanding of the environmental signals regulating neurogenesis in the adult brain and could have significant implications for the design of novel treatment strategies for Parkinson's disease.

Epidemiological studies of the Guamanian variants of amyotrophic lateral sclerosis (ALS) and parkinsonism, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), have shown a positive correlation between consumption of washed cycad seed flour and disease occurrence. Previous in vivo studies by our group have shown that the same seed flour induces ALS and PDC phenotypes in out bred adult male mice. In vitro studies using isolated cycad compounds have also demonstrated that several of these are neurotoxic, specifically, a number of water insoluble phytosterol glucosides of which β-sitosterol β-D-glucoside (BSSG) forms the largest fraction. BSSG is neurotoxic to motor neurons and other neuronal populations in culture. The present study shows that an in vitro hybrid motor neuron (NSC-34) culture treated with BSSG undergoes a dose-dependent cell loss. Surviving cells show increased expression of HSP70, decreased cytosolic heavy neurofilament expression, and have various morphological abnormalities. CD-1 mice fed mouse NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript chow pellets containing BSSG for 15 weeks showed motor deficits and motor neuron loss in the lumbar and thoracic spinal cord, along with decreased glutamate transporter labelling, and increased glial fibrillary acid protein reactivity. Other pathological outcomes included increased caspase-3 labelling in the striatum and decreased tyrosine-hydroxylase labelling in the striatum and substantia nigra. C57BL/6 mice fed BSSG-treated pellets for 10 weeks exhibited progressive loss of motor neurons in the lumbar spinal cord that continued to worsen even after the BSSG exposure ended. These results provide further support implicating sterol glucosides as one potential causal factor in the motor neuron pathology previously associated with cycad consumption and ALS-PDC.

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