Brain : a journal of neurology
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Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide alpha-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. ⋯ AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.
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Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. ⋯ MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.
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The aim of this study was to determine whether trigeminal nerve discharge associated with painful stimulation of the temple would intensify symptoms of motion sickness in migraine sufferers. If so, this would support the notion that symptoms such as nausea and headache interact with each other during attacks of migraine. Symptoms of motion sickness were rated at 2 min intervals during 15 min of optokinetic stimulation in 27 migraine sufferers and 23 age- and sex-matched controls. ⋯ In the absence of painful stimulation, increases in pulse amplitude during optokinetic stimulation were greater in migraine sufferers than controls, possibly because the discomfort associated with motion sickness triggered extracranial vasodilatation in migraine sufferers as part of a fight-or-flight (defense) response. Extracranial vasodilatation did not differ between migraine sufferers and controls when ice was applied to the temple or hand during optokinetic stimulation, implying that the additional discomfort associated with painful stimulation of the head and hand evoked a defense response in controls. These findings suggest that a mechanism which boosts extracranial neurovascular reflexes to stress and which heightens symptoms of motion sickness, increases susceptibility to migraine.
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Previous studies have suggested that an increased production of the pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) can influence patient outcome following a severe head injury. However, these studies have relied upon measurements of cytokine levels in CSF or serum, rather than the brain parenchyma itself. Recently, a method of intracranial microdialysis has been developed which permits the efficient recovery of macromolecules from the parenchyma. ⋯ Also, there was a significant correlation between peak IL-6 levels and Glasgow outcome scores (r(2) = 0.34, P = 0.03, n = 14). The levels of IL-1beta and NGF were similar in both groups of patients. From these data, we suggest that IL-6 is an endogenous neuroprotective cytokine produced in response to severe head trauma.
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In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but failed to improve impaired motor preparation. PET studies indicate that subthalamic nucleus (STN) stimulation partly reverses the abnormal premotor pattern of brain activation during movement. ⋯ In Parkinson's disease, STN stimulation may induce a change in abnormal cortical oscillatory activity patterns (similar to that produced by l-dopa) by decreasing the abnormal spreading of desynchronization over frontocentral regions and increasing PSM cortex activity during movement preparation and execution, with a correlated improvement in bradykinesia. Parkinsonians under treatment displayed a desynchronization pattern close to that seen in healthy, age-matched controls, although central latencies remained shorter. The study indicates that it is possible to influence cortical reactivity related to the planning and execution of voluntary movement through the basal ganglia, and furthermore that the oscillatory activity of the PSM cortex (in addition to that of premotor areas) could be of major importance in the control of movement-associated, neural activity in Parkinson's disease.