Experimental neurology
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Experimental neurology · May 2007
Effects of 6-hydroxydopamine-induced severe or partial lesion of the nigrostriatal pathway on the neuronal activity of pallido-subthalamic network in the rat.
The origin of changes in the neuronal activity of the globus pallidus (GP) and the subthalamic nucleus (STN) in animal models of Parkinson's disease (PD) is still controversial. The aim of the study was to investigate the neuronal activity of STN and GP neurons under urethane anesthesia in an early and in an advanced stage PD rat model. 6-Hydroxydopamine (6-OHDA) injection into the striatum induced a partial lesion of dopamine cells in the substantia nigra pars compacta (SNc) and fibers in the striatum. The GP firing rate decreased significantly with no significant change of the pattern. 6-OHDA injection into the SNc induced a total or subtotal lesion without any change in the firing rate and patterns of GP neurons. ⋯ We showed that the pathological activity of STN neurons after severe lesion is not mediated by the GP. Moreover, the unchanged activity of GP neurons is likely to be a consequence of the STN hyperactivity. These data suggest that in the GP-STN-GP network, the excitatory influence of the STN-GP pathway overrides that of the GABAergic GP-STN pathway, questioning the classical model of basal ganglia organization.
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Experimental neurology · May 2007
Randomized Controlled TrialReaction to topical capsaicin in spinal cord injury patients with and without central pain.
Central neuropathic pain is a debilitating and frequent complication to spinal cord injury (SCI). Excitatory input from hyperexcitable cells around the injured grey matter zone is suggested to play a role for central neuropathic pain felt below the level of a spinal cord injury. Direct evidence for this hypothesis is difficult to obtain. ⋯ Touch, punctuate stimuli, cold stimuli and topical capsaicin was applied above, at, and below injury level in 10 SCI patients with central pain below a thoracic injury, in 10 SCI patients with a thoracic injury but without neuropathic pain, and in corresponding areas in 10 healthy control subjects. The study found increased responses to touch at injury level compared to controls (p=0.033) and repetitive punctuate stimuli above and at injury level compared to controls and pain-free SCI patients (p<0.04) but not an increased response to capsaicin in patients with central pain. These results suggest that SCI patients with below-level pain have increased responses to some but not all sensory input at the level of injury.
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Experimental neurology · May 2007
Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury.
Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 h and 24 h post-injury. ⋯ The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.
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Experimental neurology · May 2007
Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice.
A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. ⋯ Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.
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Experimental neurology · May 2007
Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury.
We assessed the temporal and spatial characteristics of PN-induced oxidative damage and its relationship to calpain-mediated cytoskeletal degradation and neurodegeneration in a severe unilateral controlled cortical impact (CCI) traumatic brain injury (TBI) model. Quantitative temporal time course studies were performed to measure two oxidative damage markers: 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) at 30 min, 1, 3, 6, 12, 24, 48, 72 h and 7 days after injury in ipsilateral cortex of young adult male CF-1 mice. Secondly, the time course of Ca(++)-activated, calpain-mediated proteolysis was also analyzed using quantitative western-blot measurement of breakdown products of the cytoskeletal protein alpha-spectrin. ⋯ In the immunostaining study, the PN-selective marker, 3NT, and the lipid peroxidation marker, 4HNE, were intense and overlapping in the injured cortical tissue. alpha-Spectrin breakdown products, which were used as biomarker for calpain-mediated cytoskeletal degradation, were also increased after injury, but the time course lagged behind the peak of oxidative damage and did not reach its maximum until 24 h post-injury. In turn, cytoskeletal degradation preceded the peak of neurodegeneration which occurred at 48 h post-injury. These studies have led us to the hypothesis that PN-mediated oxidative damage is an early event that contributes to a compromise of Ca(++) homeostatic mechanisms which causes a massive Ca(++) overload and calpain activation which is a final common pathway that results in post-traumatic neurodegeneration.