Experimental neurology
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Experimental neurology · Feb 2010
Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies.
Alpha-synuclein (alpha-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the alpha-synucleinopathies. The mechanisms underlying alpha-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and alpha-syn may play a role. Cholesterol has been linked to alpha-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate alpha-syn fibrillization. ⋯ Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized alpha-syn in lovastatin-treated alpha-syn Tg mice in comparison to saline-treated alpha-syn Tg controls. The reduced alpha-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce alpha-syn aggregation and associated neuropathology and support the possibility that treatment with cholesterol-lowering agents may be beneficial for patients with PD and/or DLB.
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Experimental neurology · Feb 2010
Activation of lateral parabrachial afferent pathways and endocrine responses during sodium appetite regulation.
Modulation of salt appetite involves interactions between the circumventricular organs (CVOs) receptive areas and inhibitory hindbrain serotonergic circuits. Recent studies provide support to the idea that the serotonin action in the lateral parabrachial nucleus (LPBN) plays an important inhibitory role in the modulation of sodium appetite. The aim of the present work was to identify the specific groups of neurons projecting to the LPBN that are activated in the course of sodium appetite regulation, and to analyze the associated endocrine response, specifically oxytocin (OT) and atrial natriuretic peptide (ANP) plasma release, since both hormones have been implicated in the regulatory response to fluid reestablishment. ⋯ The present study identifies specific groups of neurons along the paraventricular nucleus, central extended amygdala, insular cortex, dorsal raphe nucleus, nucleus of the solitary tract and the CVOs that are activated during the modulation of sodium appetite and have direct connections with the LPBN. It also shows that OT and ANP are released during the course of sodium satiety and fluid reestablishment. The result of this brain network activity may enable appropriate responses that re-establish the body fluid balance after induced sodium consumption.
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Experimental neurology · Jan 2010
Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons.
In adult stroke models, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a sigma receptor agonist, attenuates activity of neuronal nitric oxide synthase (nNOS), blunts ischemia-induced nitric oxide production, and provides neuroprotection. Here, we tested the hypothesis that PPBP attenuates neuronal damage in a model of global hypoxia-ischemia (H-I) in newborn piglets. Piglets subjected to hypoxia followed by asphyxic cardiac arrest were treated with saline or two dosing regimens of PPBP after resuscitation. ⋯ The latter effect was associated with changes in the coupling of nNOS to postsynaptic density-95 (PSD-95), but not NR2-PSD-95 interactions. Moreover, PPBP suppressed NOS activity in the membrane fraction and reduced H-I-induced nitrative and oxidative damage to proteins and nucleic acids. These findings indicate that PPBP protects striatal neurons in a large animal model of neonatal H-I and that the protection is associated with decreased coupling of nNOS to PSD-95.
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Experimental neurology · Jan 2010
A bilateral cervical contusion injury model in mice: assessment of gripping strength as a measure of forelimb motor function.
Here, we describe a bilateral cervical contusion model for mice. Adult female mice received graded bilateral contusion injuries at cervical level 5 (C5) using a commercially available impactor (the IH device). Three separate experiments were carried out to define conditions that produce impairments in forelimb function without unacceptable impairment of general health. ⋯ Most lesions filled in with a fibrous tissue matrix, but fluid-filled cystic cavities were found in 13% of the 100 kdyn injury group and a combination of fibrous-filled/fluid-filled cystic cavities were found in 22% and 38% of the 75-kdyn and 100-kdyn injury groups, respectively. There was minimal urine retention following cervical contusion injuries indicating preservation of bladder function. Our results define conditions to produce graded bilateral cervical contusion injuries in mice and demonstrate the usefulness of the GSM for assessing forelimb motor function after cervical contusions.
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Experimental neurology · Jan 2010
Schwann cells engineered to express the cell adhesion molecule L1 accelerate myelination and motor recovery after spinal cord injury.
Functional recovery after spinal cord lesion remains an important goal. A combination of inhibitory molecules and lack of appropriate permissive factors in the lesioned spinal cord results in failure of fiber tract reconnection and function. Experimental transplantation in rodent and primate models of CNS injuries has led to the idea that Schwann cells (SCs) are promising candidates for autologous transplantation to assist myelination of lesions and to deliver therapeutic agents in the CNS. ⋯ Morphological analysis indicated that the accelerated functional recovery correlated with earlier and enhanced myelination by both grafted and host SCs. Moreover, increased sprouting of serotonergic fibers into and across the lesion site was observed in the L1/L1-Fc group as compared with controls. Our results suggest that transplantation of L1-overexpressing SCs enhances early events in spinal cord repair after injury and may be considered in combinatorial strategies together with other regeneration-promoting molecules.