Experimental neurology
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Experimental neurology · Nov 2009
Defining the mechanisms that underlie cortical hyperexcitability in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis [ALS] is a rapidly progressive neurodegenerative disorder of motor neurons, heralded by the development of cortical hyperexcitability. Reduction of short interval intracortical inhibition [SICI] in ALS, a feature linked to the development of cortical hyperexcitability, may be mediated by degeneration of inhibitory circuits or alternatively activation of high threshold excitatory circuits. As such, determining the mechanisms of SICI reduction in ALS has clear diagnostic and therapeutic significance. ⋯ In addition, the resting motor threshold was reduced, while the motor evoked potential amplitude was increased in ALS patients, in keeping with cortical hyperexcitability. These findings establish that SICI reduction in ALS represents degeneration of inhibitory cortical circuits, combined with excessive excitation of high threshold excitatory pathways. Neuroprotective strategies aimed at preserving the integrity of intracortical inhibitory circuits, in addition to antagonizing excitatory cortical circuits, may provide novel therapeutic targets in ALS.
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There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague-Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. ⋯ Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted.
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Experimental neurology · Nov 2009
Methylprednisolone fails to improve functional and histological outcome following spinal cord injury in rats.
Currently, methylprednisolone sodium succinate (MPSS) is the standard treatment following acute spinal cord injury (SCI) as a consequence of the results obtained from the National Acute Spinal Cord Injury Studies. However, many have questioned the efficacy of MPSS because of its marginal effects. Additionally there has been criticism of both study design and statistical interpretation. ⋯ More importantly, the results of the 3D kinematic showed that the MPSS administration did not affect the flexion/extension of the hip, knee and ankle joints during the step cycle. Finally, stereological results revealed no statistically significant differences between the two experimental groups. Altogether, our results support data previously reported by several authors, suggesting that MPSS does not lead to improved functional outcome following experimental acute SCI.
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Experimental neurology · Oct 2009
ReviewHuntington's disease: the current state of research with peripheral tissues.
Huntington's disease (HD) is a genetically dominant condition caused by expanded CAG repeats. These repeats code for a glutamine tract in the HD gene product huntingtin (htt), which is a protein expressed in almost all tissues. ⋯ These studies show that in peripheral tissues, mutated htt causes accumulation of intracellular protein aggregates, impairment of energetic metabolism, transcriptional deregulation and hyperactivation of programmed cell-death mechanisms. Here, we review the current knowledge of peripheral tissue alterations in HD patients and in animal models of HD and focus on how this information can be used to identify potential therapeutic possibilities and biomarkers for disease progression.
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Experimental neurology · Oct 2009
Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway.
Human tissue kallikrein (hTK) gene transfer has been shown to protect neurons against cerebral ischemia/reperfusion (I/R) injury, and exogenous tissue kallikrein (TK) administration can enhance neurogenesis and angiogenesis following focal cortical infarction. Previous studies have reported that acidosis is a common feature of ischemia and plays a critical role in brain injury. However, little is known about the role of TK in ischemia-acidosis-induced injury, which is partially caused by the activation of acid-sensing ion channels (ASICs). ⋯ Moreover, blockade of ASICs had effects similar to TK administration, suggesting direct or indirect involvement of ASICs in TK protection. In conclusion, TK has antioxidant characteristics and is capable of alleviating ischemia-acidosis/reperfusion-induced injury, inhibiting apoptosis and promoting cell survival in vitro through activating the ERK1/2 signaling pathways. Therefore, TK represents a promising therapeutic strategy for ischemic stroke.