Experimental neurology
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Experimental neurology · Dec 2008
Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.
The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. ⋯ In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.
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Experimental neurology · Dec 2008
Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function.
The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin alpha4beta1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrin's functions may afford significant neuroprotection. ⋯ At 2-4 weeks after SCI, anti-alpha4beta1 treatment decreased blood pressure responses during autonomic dysreflexia by as much as 43% and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw by up to 54% and 40%, respectively. This improved functional recovery correlated with spared myelin-containing white matter and >10-fold more bulbospinal serotonergic axons below the injury than were in controls. The significant neurological improvement offered by this neuroprotective strategy underscores the potential for an anti-integrin treatment for SCI.
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Experimental neurology · Dec 2008
Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy.
Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague-Dawley rats 2-6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L(3-4)) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons approximately 40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by approximately 60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. ⋯ These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.
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Experimental neurology · Dec 2008
An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury.
Our previous studies have shown that treatment with an alpha4beta1 integrin blocking antibody after spinal cord injury (SCI) in rats decreases intraspinal inflammation and oxidative damage, improving neurological function. Here, we studied effects of a high affinity small molecule alpha4beta1 inhibitor, BIO5192. First, rats were treated intravenously with BIO5192 (10 mg/kg) or with vehicle (controls) to assess effects of integrin blockade for 24 h or 72 h after thoracic clip-compression SCI. ⋯ BIO5192 treatment also decreased mechanical allodynia elicited from the trunk and hind paw by up to 35%. This improved function correlated with decreased lesion size and spared myelin-containing white matter. The neurological improvement offered by this neuroprotective strategy supports the potential for an anti-integrin treatment for SCI.
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Experimental neurology · Dec 2008
Effects of combined dorsolateral and dorsal funicular lesions on sensorimotor behaviour in rats.
The purpose of this research was to investigate the compensatory role of undamaged spinal pathways after partial spinal injury in rats. We have previously shown that bilateral lesions of the dorsal funiculus (DF) at the cervical level caused changes in overground and skilled locomotion that affected the forelimbs more than the hindlimbs. The same lesions also caused fore-paw deficits during a skilled pellet retrieval task (Kanagal and Muir, 2007). ⋯ During both ladder crossing and reaching, secondary lesions to DF (with or without CST) exacerbated the deficits seen after initial DLF lesions and additionally caused changes in the manner in which the rats used their forelimbs during reaching. Nevertheless, the relative magnitude of the deficits indicates that DF pathways in rats likely do not compensate for loss of DLF pathways during the execution of locomotor tasks, though there is indirect evidence that DLF-lesioned rats might rely more on ascending sensory pathways in the DF during skilled forelimb movements. The plastic changes mediating recovery are therefore necessarily occurring in other regions of the CNS, and, importantly, need time to develop, because animals with DLF+DF lesions performed simultaneously displayed marked functional deficits and were unable to use their forelimbs for skilled locomotion or reaching.