Bmc Neurosci
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Randomized Controlled Trial
Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-α.
Tumor necrosis factor-alpha (TNF-α) is elevated early in injured brain after traumatic brain injury (TBI), in humans and in animals. Etanercept (a TNF-α antagonist with anti-inflammatory effects) attenuates TBI in rats by reducing both microglial and astrocytic activation and increased serum levels of TNF-α. However, it is not known whether etanercept improves outcomes of TBI by attenuating microglia-associated, astrocytes-associated, and/or neurons-associated TNF-α expression in ischemic brain. A well clinically relevant rat model, where a lateral fluid percussion is combined with systemic administration of etanercept immediately after TBI, was used. The neurological severity score and motor function was measured on all rats preinjury and on day 3 after etanercept administration. At the same time, the neuronal and glial production of TNF-α was measured by Immunofluorescence staining. In addition, TNFα contents of ischemic cerebral homogenates was measured using commercial enzyme-linked immunosorbent assay kits. ⋯ This finding indicates that early microglia overproduction of TNF-α in the injured brain region after TBI contributes to cerebral ischemia and neurological motor deficits, which can be attenuated by etanercept therapy. Studies in this model could provide insight into the mechanisms underlying neurological motor disturbance in brain-injured patients.
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The nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex that induces complex muscle synergies to withdraw a limb from a potential noxious stimulus. Several studies indicate that assessment of the NWR is a valuable objective tool in relation to investigation of various pain conditions. However, existing methodologies for NWR assessment evaluate standard surface electromyography (sEMG) measured over just one muscle and do not consider the possible interference of crosstalk originating from adjacent active muscles. The present study had two aims: firstly, to investigate to which extent the presence of crosstalk may affect NWR detection using a standardized scoring criterion (interval peak z-score) that has been validated without taking crosstalk into consideration. Secondly, to investigate whether estimation of muscle fiber conduction velocity can help identifying the propagating and non-propagating nature of genuine reflexes and crosstalk respectively, thus allowing a more valid assessment of the NWR. ⋯ This study investigated the negative effect of electrical crosstalk during reflex detection and revealed that the use of a previously validated scoring criterion may result in poor specificity due to crosstalk. The excellent performance of the developed methodology in the presence of crosstalk shows that assessment of muscle fiber conduction velocity allows reliable detection of EMG crosstalk during reflex detection.
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The cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) is affected by changes in TMS intensity. Some studies have shown that CSP is shortened or prolonged by short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), Those studies, however, used different TMS intensities to adjust the amplitude of the motor evoked potential (MEP). Therefore, it is unclear whether changes in CSP duration are induced by changes in TMS intensities or by SICI and ICF. The purpose of this study was to confirm the effects of muscle contractions and stimulus intensities on MEP amplitude and the duration of CSP induced by single-pulse TMS and to clarify the effects of SICI and ICF on CSP duration.MEP evoked by TMS was detected from the right first dorsal interosseous muscle in 15 healthy subjects. First, MEP and CSP were induced by single-pulse TMS with an intensity of 100% active motor threshold (AMT) at four muscle contraction levels [10%, 30%, 50%, and 70% electromyogram (EMG)]. Next, MEP and CSP were induced by seven TMS intensities (100%, 110%, 120%, 130%, 140%, 150%, and 160% AMT) during muscle contraction of 10% EMG. Finally, SICI and ICF were recorded at the four muscle contraction levels (0%, 10%, 30%, and 50% EMG). ⋯ We confirmed that CSP duration is affected by TMS intensity but not by the muscle contraction level. This study demonstrated that CSP is shortened with SICI, but it is not altered with ICF. These results indicate that after SICI, CSP duration is affected by the activity of inhibitory intermediate neurons that are activated by the conditioning SICI stimulus.
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Upregulation of vasoconstrictor receptors in cerebral arteries, including endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors, has been suggested to contribute to delayed cerebral ischemia, a feared complication after subarachnoid hemorrhage (SAH). This receptor upregulation has been shown to be mediated by intracellular signalling via the mitogen activated protein kinase kinase (MEK1/2)--extracellular regulated kinase 1/2 (ERK1/2) pathway. However, it is not known what event(s) that trigger MEK-ERK1/2 activation and vasoconstrictor receptor upregulation after SAH.We hypothesise that the drop in cerebral blood flow (CBF) and wall tension experienced by cerebral arteries in acute SAH is a key triggering event. We here investigate the importance of the duration of this acute CBF drop in a rat SAH model in which a fixed amount of blood is injected into the prechiasmatic cistern either at a high rate resulting in a short acute CBF drop or at a slower rate resulting in a prolonged acute CBF drop. ⋯ Our findings suggest a series of events where 1) the acute CBF drop triggers early MEK-ERK1/2 activation, which 2) triggers the transcriptional upregulation of vasoconstrictor receptors in cerebral arteries during the following days, where 3) the resulting enhanced cerebrovascular contractility contribute to delayed cerebral ischemia.
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Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis. ⋯ The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.