Immunomodulatory Effect of Combination Therapy with Lovastatin and 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Alleviates Neurodegeneration in Experimental Autoimmune Encephalomyelitis

Abstract

Combination therapy with multiple sclerosis (MS) therapeutics is gaining momentum over monotherapy for improving MS. Lovastatin, an HMG-CoA reductase inhibitor (statin), was immunomodulatory in an experimental autoimmune encephalomyelitis (EAE) model of MS. Lovastatin biases the immune response from Th1 to a protective Th2 response in EAE by a different mechanism than 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside, an immunomodulating agent that activates AMP-activated protein kinase. Here we tested these agents in combination in an EAE model of MS. Suboptimal doses of these drugs in combination were additive in efficacy against the induction of EAE; clinical symptoms were delayed and severity and duration of disease was reduced. In the central nervous system, the cellular infiltration and proinflammatory immune response was decreased while the anti-inflammatory immune response was increased. Combination treatment biased the class of elicited myelin basic protein antibodies from IgG2a to IgG1 and IgG2b, suggesting a shift from Th1 to Th2 response. In addition, combination therapy lessened inflammation-associated neurodegeneration in the central nervous system of EAE animals. These effects were absent in EAE animals treated with either drug alone at the same dose. Thus, our data sug- Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that mimics many aspects of multiple sclerosis (MS). 1Pathophysiology of EAE includes breaching of the blood brain barrier, infiltration of mononuclear cells-predominantly myelin-reactive CD4 ϩ and CD8 ϩ T-cells and macrophages, resulting in the activation of resident CNS glial cells.2 Different from EAE, however, myelin-reactive CD8 ϩ T cells play a major role in MS pathogenesis.3 On activation CNS glial cells secrete proinflammatory mediators [cytokines, chemokines, and inducible nitric oxide (NO) synthase] and activate complement cascade pathways. 4 These events produce excitotoxic and oxidative damage because of the depletion of intracellular energy stores, destabilization of the cell membrane, opening of voltage-gated Ca 2ϩ channels, and activation of NMDA receptors in neurons and oligodendrocytes. [5][6][7] Moreover, depletion of ATP in astrocytes during EAE leads to mitochondrial malfunction and cellular energy failure, contributing to neuron loss. 8,9 Consequently, these inflammatory events lead to CNS demyelination because of degradation of the myelin sheath and a loss of both oligodendrocytes and neuronal axons in the CNS.

Inhibition of Rho Family Functions by Lovastatin Promotes Myelin Repair in Ameliorating Experimental Autoimmune Encephalomyelitis

“…Likewise, atorvastatin, a related drug was promising in rheumatoid arthritis patients (McCarey et al, 2004). The disease-modifying effects of statins in the animal model of MS are attributed to the following: inhibition of cellular infiltration (Paintlia et al, 2004), activation of immune cells (i.e., macrophages, T cells, and endothelial cells) (Youssef et al, 2002;Paintlia et al, 2004), breakdown of the blood-brain barrier (Greenwood et al, 2003), and neurodegeneration (Paintlia et al, 2005(Paintlia et al, , 2006b.…”

Statins—Treatment Option for Central Nervous System Autoimmune Disease?

“…Encouraging results were also obtained from testing the combination of atorvastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an immunomodulating agent that activates AMP-activated protein kinase. 50 This combination was an additive for EAE prevention and reduced cellular infiltration of the CNS more than either drug alone. In addition, this combination lessened axonal loss, which might be of particular interest for treatment of MS at the later neurodegenerative stage.…”

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…The expression of antibodies against oligodendrocytes and their progenitors [64,65], and activation of AMPA/kainite receptors by increased amounts of glutamate [66], are some of the factors that are reported to account for the observed demyelination in inflammatory areas in MS plaques. Reparative therapies with a potential to enhance remyelination, such as statins, provide a promising approach for myelin repair [10,68,69]. Higher numbers of oligodendrocyte progenitors in the spinal cords of animals with EAE treated with lovastatin and their observed proliferation and differentiation into myelin-producing cells document the potential of statins to repair demyelinated lesions [10].…”

“…However, the precise role of these factors in the loss of oligodendrocytes and myelin in MS is not well understood. Recent studies reporting reduced loss of myelin proteins and lipids in the brains and spinal cord of animals with EAE treated with lovastatin [10], or a lovastatin and 5 aminoimidazole-4-carboxamide ribonucleoside (AICAR) combination [68], suggest the possible neuroprotective activity of lovastatin against loss of oligodendrocytes and myelin in EAE.…”

“…Therefore, the best way to prevent disease progression in MS is to prevent demyelination, protect oligodendrocyte progenitors and promote remyelination. Lovastatin treatment of EAE rats has been reported to meet these criteria [10,68].…”