Experimental neurology
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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
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.