Dexpramipexole alleviates chronic allodynia from sciatic neuropathy and reduces spinal interferon-g (IFN-g) and other proinflammatory cytokines in spinal cord and DRG in mice.

Abstract

Dexpramipexole (DPX) is a small molecule compound with properties previously shown to block the voltage-gated sodium channel, Nav1.8 on nociceptors. It additionally has anti-inflammatory properties in immune cells. In addition to clinical trials investigating the therapeutic efficacy of DPX to control eosinophilic asthma, DPX is effective in alleviating peripheral neuropathies in preclinical mouse models such as sciatic nerve chronic constriction injury (CCI), effectively reversing pathological sensitivity to light touch (i.e. allodynia). Pain signals are further processed in limbic areas of the brain that serve to regulate stress. Such overlapping regulation elicits increases in hypothalamic efferent sympathetic activity, which engages the spleen and adrenal glands in response to stress; organs critical in regulating immune responses and producing catecholaminergic norepinephrine (NE), respectively. Thus, the current study evaluated the action of DPX on the (1) full timecourse of peripheral (intravenous, i.v.) DPX, and the acute timecourse of spinal (intrathecal, i.t.) DPX on established allodynia from CCI, and (2) characterized spinal and limbic proinflammatory cytokine protein expression following the spinal i.t. DPX application in female mice. Splenic cytokine mRNA expression and adrenal NE levels were measured, as CCI-induced neuropathy elicits elevated sympathetic nervous activity. Hindpaw sensitivity was assessed using the von Frey method. After i.t. DPX and hindpaw reassessment at 1hr, the anterior cingulate cortex, amygdala, hypothalamus, dorsal lumbar spinal cord, lumbar dorsal root ganglia (DRG), spleen and adrenal glands were collected. After i.v. DPX, a profound allodynic reversal within 1hr through 24hrs, that returned by 48hr occurred After i.t. DPX, full reversal of allodynia by 1hr occurred. CCI-induced elevations in spinal interferon gamma (IFN-?) protein was significantly suppressed from i.t. DPX mice demonstrating allodynia reversal, whereas trends for reduced spinal interleukin-1b (IL-1?) and tumor necrosis factor-? (TNF?) were observed. Lumbar DRG from allodynic revered mice given i.t. DPX revealed reduced IL-1? and TNF?, as was observed in the hypothalamus. I.t. DPX didn't reliably alter splenic cytokine mRNA expression nor adrenal NE. These data suggest DPX may control allodynia by decreasing spinal IFN-? and sensory ganglia IL-1? and TNF?, which may serve as a potential pain therapeutic in addition to its action at Nav1.8.