Experimental neurology
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Experimental neurology · May 2002
Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice.
Human alpha-synuclein (halpha-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. ⋯ Adult hwalpha-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2alpha-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.
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Experimental neurology · Feb 2002
Relationship between functional deficiencies and the contribution of myelin nerve fibers derived from L-4, L-5, and L-6 spinolumbar branches in adult rat sciatic nerve.
The distribution and relative intrafascicular contribution of myelin fibers derived from spinal segments L-4 to L-6 were analyzed in adult rat sciatic nerve and its main branches, using 200-kDa neurofilament subunit immunodetection in previously injured nerve sections in the L-4 or L-5 spinal branch or both. These branches' functional contribution was evaluated 16 days after the injury, using the method of J. Bain, S. ⋯ Injury to L-5 caused a significant reduction in the sciatic (SFI) and tibial (TFI) functional nerve indices, an increase in PL, and a reduction in the spread between opposite toes (TS). Finally, transection of both L-4 and L-5 was followed by a significant reduction in all functional indices measured, an increase in PL, and a reduction in intermediate toe (ITS) and opposite toe spread (TS). The results indicate a direct relationship between the distribution and contribution of the spinal nerve fibers forming the sciatic nerve and the alteration in functional indices for sciatic, tibial, and peroneal nerves.
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Experimental neurology · Jan 2002
Induction of type IV collagen and other basement-membrane-associated proteins after spinal cord injury of the adult rat may participate in formation of the glial scar.
We investigated the spatial and temporal expression of basement-membrane-forming and neurite-outgrowth-supporting matrix proteins after a unilateral dorsal root injury combined with a collagen I/laminin-1 graft and a stab wound lesion to the dorsal horn of the adult rat spinal cord. Ten days after injury, the gamma1 laminin was induced in the reactive glia. At this early stage, the glial cells failed to express type IV collagen and the alpha1 laminin. ⋯ Induction of type IV collagen in astrocytes in vitro by cytokines indicates that blood-borne or local factors at the injury site may induce the spinal cord glial expression of type IV collagen in vivo. Simultaneous expression of laminin-1 and alpha1 laminin with type IV collagen is known to lead to production of basement membranes. This may hamper the neurite-outgrowth-promoting potential of the gamma1 laminin by initiating formation of the glial scar.
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Experimental neurology · Jan 2002
Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival.
At focal CNS injury sites, several cytokines accumulate, including ciliary neurotrophic factor (CNTF) and interleukin-1beta (IL-1beta). Additionally, the CNTF alpha receptor is induced on astrocytes, establishing an autocrine/paracrine loop. How astrocyte function is altered as a result of CNTF stimulation remains incompletely characterized. ⋯ These findings demonstrate that cytokine-activated astrocytes better support CNS neuron survival via the production of neurotrophic molecules. We also show that CNTF synergizes with FGF-2, but not epidermal growth factor, to promote DNA synthesis in spinal cord astrocyte cultures. The significance of these findings is discussed by presenting a new model depicting the sequential activation of astrocytes by cytokines and growth factors in the context of CNS injury and repair.
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Experimental neurology · Dec 2001
Effect of creatine supplementation on metabolite levels in ALS motor cortices.
Mitochondrial pathology is an early observation in motor neurons and skeletal muscle of patients with amyotrophic lateral sclerosis (ALS). To clarify the relevance of this finding, we determined the effects of a 1-month oral administration of creatine on (1)H NMR-visible metabolites in the motor cortices of 15 controls and 15 patients with sporadic ALS, most of whom had mitochondrial pathology in skeletal muscle. In the motor cortex of the ALS group the N-acetylaspartate (NAA)/creatine (Cr(t)) metabolite ratio was lower than in our control group, indicating NAA loss. ⋯ In contrast, in the ALS patient group the NAA/Cr(t) and the NAA/Cho metabolite ratios remained unchanged, while the Glx/Cr(t) and Glx/Cho metabolite ratios decreased. These data are compatible with the interpretation that creatine supplementation causes an increase in the diminished NAA levels in ALS motor cortex as well as an increase of choline levels in both ALS and control motor cortices. Because NAA is synthesized by mitochondria in an energy-dependent manner and the NAA/Cho metabolite ratios in the ALS motor cortices were found to be correlated to the degree of mitochondrial pathology in ALS skeletal muscle, our results can be explained by a deficiency of enzymes of mitochondrial respiratory chain in the ALS motor cortex which might affect motor neuron survival.