Dexpramipexole alleviates chronic allodynia from sciatic neuropathy and reduces spinal interferon-γ and other proinflammatory cytokines in spinal cord and dorsal root ganglia in mice.

Abstract

Dexpramipexole is a small molecule compound with properties previously shown to block the voltage-gated sodium channel, Nav_1.8 on nociceptors. It additionally has anti-inflammatory properties in immune cells. In addition to clinical trials investigating the therapeutic efficacy of dexpramipexole to control eosinophilic asthma, dexpramipexole is effective in alleviating peripheral neuropathies in preclinical mouse models such as sciatic nerve chronic constriction injury, which reverses 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, respectively. Thus, the current study evaluated the action of dexpramipexole (1) on the full timecourse of peripheral (intravenous) dexpramipexole and the acute timecourse of spinal (intrathecal) dexpramipexole on established allodynia from chronic constriction injury, and (2) characterized spinal and limbic proinflammatory cytokine protein expression following the spinal intrathecal dexpramipexole application in female mice. Splenic cytokine mRNA expression and adrenal norepinephrine levels were measured, as chronic constriction injury-induced neuropathy elicits elevated sympathetic nervous activity. Hindpaw sensitivity was assessed using the von Frey method. After intrathecal dexpramipexole and hindpaw reassessment at 1hr, the anterior cingulate cortex, amygdala, hypothalamus, dorsal lumbar spinal cord, lumbar dorsal root ganglia, spleen and adrenal glands were collected. Intravenous dexpramipexole, resulted in profound allodynic reversal within 1hr through 24hr, that returned by 48hr occurred. Intrathecal dexpramipexole, resulted in full reversal of allodynia by 1hr occurred. Chronic constriction injury-induced elevations in spinal interferon-γ protein was significantly suppressed from intrathecal dexpramipexole-treated mice that also demonstrated allodynia reversal, whereas trends for reduced spinal interleukin-1β and tumor necrosis factor-α were observed. Lumbar dorsal root ganglia from allodynic reversed mice given intrathecal dexpramipexole revealed reduced interleukin-1β and tumor necrosis factor-α, as was observed in the hypothalamus. Intrathecal dexpramipexole did not reliably alter splenic cytokine mRNA expression nor adrenal norepinephrine. These data suggest dexpramipexole may control allodynia by decreasing spinal interferon-γ and sensory ganglia interleukin-1β and tumor necrosis factor-α, which may serve as a potential pain therapeutic in addition to its action at Nav_1.8.