Experimental neurology
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Experimental neurology · Mar 1999
Comparative StudyComparing deficits following excitotoxic and contusion injuries in the thoracic and lumbar spinal cord of the adult rat.
The majority of human spinal cord injuries involve gray matter loss from the cervical or lumbar enlargements. However, the deficits that arise from gray matter damage are largely masked by the severe deficits due to associated white matter damage. We have developed a model to examine gray matter-specific deficits and therapeutic strategies that uses intraspinal injections of the excitotoxin kainic acid into the T9 and L2 regions of the spinal cord. ⋯ Kainic acid injections into T9 resulted in substantial gray matter damage; however, BBB scores and tcMMEP response latencies were not different from those of controls. In contrast, kainic acid injections into L2 resulted in paraplegia with BBB scores similar to those following contusion injuries at either T9 or L2, without affecting tcMMEP response latencies. These observations demonstrate that gray matter loss can result in significant functional deficits, including paraplegia, in the absence of a disruption of major descending pathways.
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Experimental neurology · Feb 1999
Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat.
Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. ⋯ However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
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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.
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Experimental neurology · Sep 1998
Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury.
Traumatic injury to the central nervous system initiates inflammatory processes that are implicated in secondary tissue damage. These processes include the synthesis of proinflammatory cytokines, leukocyte extravasation, vasogenic edema, and blood-brain barrier breakdown. Interleukin-10 (IL-10), a cytokine with antiinflammatory properties, negatively modulates proinflammatory cascades at multiple levels. ⋯ Subcutaneous IL-10 administration (100 micrograms) at 10 min, 1, 3, 6, 9, and 12 h after TBI also enhanced neurological recovery. In contrast, intracerebroventricular administration of IL-10 (1 or 6 micrograms) at 15 min, 2, 4, 6, and 8 h after TBI was not beneficial. These results indicate that IL-10 treatment improves outcome after TBI and suggest that this improvement may relate, in part, to reductions in proinflammatory cytokine synthesis.