Statins alleviate experimental nerve injury-induced neuropathic pain

Abstract

The statins are a well-established class of drugs that lower plasma cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase. They are widely used for the treatment of hypercholesterolemia and for the prevention of coronary heart disease. Recent studies suggest that statins have anti-inflammatory effects beyond their lipid-lowering properties. We sought to investigate whether statins could affect neuropathic pain by mediating nerve injury-associated inflammatory responses. The effects of hydrophilic rosuvastatin and lipophilic simvastatin were examined in the mouse partial sciatic nerve ligation model. Systemic daily administration of either statin from days 0 to 14 completely prevented the development of mechanical allodynia and thermal hyperalgesia. When administered from days 8 to 14 after injury, both statins dose-dependently reduced established hypersensitivity. After treatment, the effects of the statins were washed out within 2 to 7 days, depending on dose. Effects of both statins in alleviating mechanical allodynia were further confirmed in a different injury-associated neuropathic pain model, mental nerve chronic constriction, in rats. Both statins were able to abolish interleukin-1β expression in sciatic nerve triggered by nerve ligation. Additionally, quantitative analysis with Iba-1 and glial fibrillary acid protein immunoreactivity demonstrated that rosuvastatin and simvastatin significantly reduced the spinal microglial and astrocyte activation produced by sciatic nerve injury. The increase of interleukin-1β mRNA in the ipsilateral side of spinal cords was also reduced by the treatment of either statin. We identified a potential new application of statins in the treatment of neuropathic pain. The pain-alleviating effects of statins are likely attributable to their immunomodulatory effects.

Gabapentin Prevents Oxaliplatin-Induced Mechanical Hyperalgesia in Mice

“…Systemic treatment with atorvastatin produced antinociceptive and antihyperalgesic effects in models of bacterial adjuvantinduced inflammatory pain (35) or lipopolysaccharideinduced pain (36). Repeated treatment with simvastatin and rosuvastatin also pro duced an antihyperalgesic effect in mice and rats with nerve injuryinduced neuropathic pain (18). Recently, we also reported that intrathecal, but not intracerebroven tricular, administration of simvastatin exerted an antino ciceptive effect in formalininduced nociception (19).…”

“…Systemic treatment with the lipidlowering drugs simvastatin and rosuvastatin attenuates thermal hyperal gesia and mechanical allodynia in nerveligated rats (18). We recently reported that intrathecal treatment with simvastatin attenuated the second, but not first, phase of the formalininduced nociceptive response, suggesting inhibition of the sensitization of spinal nociceptive trans mission (19).…”

Peripheral Nerve Injury Induces Persistent Vascular Dysfunction and Endoneurial Hypoxia, Contributing to the Genesis of Neuropathic Pain

“…Interleukin-1␤ (Scannell, 1996), interleukin-6 (Albina et al, 1995, tumor necrosis factor-␣ (Cramer et al, 2003), and CC chemokine ligand 3 (Bosco et al, 2004) are upregulated in macrophages by hypoxia. These same molecules are upregulated in macrophages in models of neuropathic pain (Shi et al, 2011;Lee and Zhang, 2012;Lim et al, 2014). It is possible that targeting hypoxia may abrogate many unwanted effects of macrophages, without affecting their beneficial functions.…”

Effect of Spinally Administered Simvastatin on the Formalin-Induced Nociceptive Response in Mice

“…It is reported that systemic treatment with atorvastatin produces antinociceptive and antihyperalgesic effects in inflammatory pain induced by bacterial adjuvant (4) or lipopolysaccharide (5). Repeated treatment with simvastatin and rosuvastatin also produces an antihyperalgesic effect in nerve injury-induced neuropathic pain in mice and rats (6). These reports suggest that these effects of HMG-CoA reductase inhibitors might be mediated by the anti-inflammatory effect.…”