Experimental neurology
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Experimental neurology · Dec 1998
Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor.
Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. ⋯ ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD.
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Experimental neurology · Dec 1998
Differential spatiotemporal alterations in adrenoceptor mRNAs and binding sites in cerebral cortex following spreading depression: selective and prolonged up-regulation of alpha1B-adrenoceptors.
Noradrenaline, an important transmitter in the CNS, is involved in cerebral plasticity and functional recovery after injury. Experimental brain injury, including KCl application onto the brain surface, induces a slow-moving cortical depolarization/depression wave called cortical spreading depression (CSD). Interestingly, CSD does not produce neuronal damage but can protect cortical neurons against subsequent neurotoxic insults, although the mechanisms involved are unknown. ⋯ In contrast, CSD had no effect on the remaining AR-subtype mRNAs or binding levels in neocortex under identical conditions. These results reveal a long-term up-regulation of alpha1B-ARs induced by an acute cortical stimulation/depression. Subtype-selective responses of ARs to CSD reflect an important differential regulation of expression of each receptor in vivo and suggest that alpha1B-ARs are particularly likely to be involved in cortical adaptive responses to physical injury at both local and distant locations.