Lovastatin attenuates nerve injury in an animal model of Guillain–Barré syndrome

Abstract

Statins, widely used as clinically effective inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, exhibit anti-inflammatory properties that may be of therapeutic benefit for the management of some neurological disorders. In this study, a short-term course of lovastatin treatment is shown to markedly inhibit the development of experimental autoimmune neuritis (EAN) in the absence of hepatotoxic or myotoxic complications. Independent of cholesterol reduction, lovastatin treatment prevented EAN-induced peripheral nerve conduction deficits and morphologic nerve injury. Co-administration with mevalonate neutralized the prophylactic effects of lovastatin. When administered therapeutically, lovastatin significantly shortened the disease course. Autoreactive immunity, measured in vitro by myelin-stimulated proliferation of splenocytes, was significantly diminished by in vivo lovastatin treatment. Th1-dominant immune responses, measured by cytokine profiling, however, were not affected by lovastatin. Sciatic nerves of lovastatin-treated immunized rats showed markedly reduced levels of cellular infiltrates. Treating peripheral nerve endothelial monolayers with lovastatin significantly inhibited the in vitro migration of autoreactive splenocytes. Together, these data demonstrate that a short-term course of lovastatin attenuates the development and progression of EAN in Lewis rats by limiting the proliferation and migration of autoreactive leukocytes.

Emerging Indications for Statins: A Pluripotent Family of Agents with Several Potential Applications

“…These results were verified in a similar rat model of experimental autoimmune myocarditis [326]. In addition, a short-term course of lovastatin treatment markedly inhibited the development of experimental autoimmune neuritis in another rat model [327]. Statins exert their effect on the immune system mainly by interaction through the Major Histocompatibility Complex class II (MHC-II) pathway, thereby identifying this route of antigen processing and presentation as a selective target of statins [328,329].…”

Novel role of Cdc42 and RalA GTPases in TNF-α mediated secretion of CCL2

“…Disrupting monomeric GTPase signaling, in vivo, with statins therapeutically attenuates development and progression of experimental autoimmune neuritis. 8 However, rare but serious (rhabdomyolysis) 34,35 and emerging (diabetes, memory loss) 36,37 side effects of statins has limited their therapeutic application. Protein prenyltransferase inhibitors may represent a more directed approach in which to target autoreactive leukocyte recruitment and trafficking (Fig.…”

“…1,2 Consequently, aberrant signaling by these GTPases is now implicated in the pathogenesis of a spectrum of seemingly disparate inflammatory disorders, 3,4 including autoimmune inflammatory demyelinating disorders. [5][6][7][8] To facilitate target membrane localization and functional activation of Rho family GTPases, newly synthesized native proteins must first undergo post-translational modification. 1,2,9 Similar to other monomeric GTPases, modification of native Rho proteins involves prenyltransferase-catalyzed addition of sesquiterpene (farnesyl) or diterpene (geranylgeranyl) isoprenoids to conserved cysteine residues localized to a carboxy terminal -CaaX motif.…”

“…9 Our lab has previously demonstrated that administration of a short-term high-dose course of statins, in vivo, elicits marked protection against the development and progression of experimental autoimmune neuritis by limiting the trafficking of macrophages and T lymphocytes into peripheral nerves. 8 These studies suggested a novel role of small monomeric GTPases in regulating cytokine-mediated transendothelial trafficking of leukocytes into peripheral nerves. Follow-up studies by our group subsequently identified geranylgeranylated GTPases as key participants in TNF-α mediated secretion of chemokine (C-C motif) ligand 2 (CCL2) from cultured peripheral nerve microvascular endoneurial endothelial cells, supporting an essential role for Rho family GTPases in regulating transendothelial trafficking of autoreactive leukocytes into peripheral nerves.…”

Update on medication-induced peripheral neuropathy

“…Experimental evidence also suggests that the statin rosuvastatin improves a mouse model of diabetic neuropathy through improved microcirculation independent of cholesterol-lowering effects [51]. Lovastatin also attenuated nerve injury in an experimental model of experimental allergic neuritis; the effect was blocked by mevalonate [52]. There is no supportive experimental model of the potentially neurotoxic effects, but alteration of membrane function through inhibition of cholesterol synthesis, reduction of axon transport, and inhibition of mitochondrial function have been suggested as possible factors.…”