Primaquine Treatment Suppresses Experimental Autoimmune Encephalomyelitis Severity

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a T cell-dependent disease that mimics human multiple sclerosis (MS). The inflammation in the central nervous system (CNS) is a hallmark in these autoimmune inflammatory conditions [1]. Therefore, the development of new drugs that target the infiltration of inflammatory cells to the CNS is desired [2,3]. In this context, accumulating evidences place antimalarial drugs as immunomodulatory agents. For instance, administration of chloroquine, a weak base that has tropism toward acidic organelles, was shown to modulate a series of inflammatory diseases, including EAE [4,5]. On the other hand, primaquine (PQ), a drug analogous to chloroquine [6], has much less toxicity and is poorly investigated in the control of inflammation.In this study, we aimed to evaluate whether PQ administration is able to reduce EAE severity. For that purpose, we induced EAE in C57BL/6 mice through subcutaneous injection of 100 lg of MOG 35-55 peptide alongside with 200 ng of pertussis toxin, as previously described [7]. When the clinical signs of EAE started to appear, mice were treated with PQ (3 mg/kg, intraperitoneally) for five consecutive days and disease outcome was evaluated (EAE+PQ group). Mice treated with vehicle (PBS) were used as controls (EAE group). We observed that PQ treatment significantly reduced the development of EAE ( Figure 1A). Interestingly, disease amelioration correlated with lower infiltration of cells in the CNS ( Figure 1B). Notwithstanding, the frequency of Iba-1 + cells (microglia, macrophages, and dendritic cells) was found reduced in the EAE+PQ group compared with untreated EAE-bearing mice, suggesting that probably the demyelination process is reduced in the CNS of EAE+PQ mice ( Figure 1B). To evaluate whether glial cells are affected by PQ treatment, slices were stained for glial fibrillary acidic protein (GFAP) production. Our results showed that EAE+PQ mice presented lower expression of GFAP in comparison with the EAE group ( Figure 1B). Of note, PQ treatment by itself did not induce GFAP expression.Collectively, these results show that improvement in EAE+PQ mice correlated with a reduction in cellular infiltration and gliosis. To investigate whether mediators of inflammation are involved in disease amelioration, the gene expression levels of inflammationrelated cytokines and transcription factors were analyzed. Results showed that levels of FOXP3, IL-10, and TGF-b were significantly increased, while the levels of TNF-a, IL-17, IFN-c, and GATA-3 were decreased in the CNS of EAE+PQ mice compared with the control ( Figure 1C). Unexpectedly, levels of Th17 cell-related transcription factor, RORct, were found reduced in EAE-bearing mice compared with na€ ıve mice, showing that modulation of this transcription factor is not a key element in PQ-induced EAE amelioration.The increased expression in FOXP3, IL-10, and TGF-b in the CNS of EAE+PQ mice suggests that the treatment induces the expansion of regulatory T (Treg) cells. To confirm this hypothesis, na€ ıve m...

Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells

“…It was previously shown that dihydroartemisinin reduced the clinical course of EAE through the inhibition of the mammalian target of rampamycin (mTOR) signaling pathway and increase in Treg numbers [ 12 ]. Likewise, we showed previously that, chloroquine, and its analogue primaquine, is able to reduce the severity of Experimental Autoimmune Encephalomyelitis through the elicitation of regulatory T cells [ 11 , 30 ]. Thus, drugs that rise Treg cells numbers are desired to control autoimmunity [ 22 , 31 ].…”

GADD45A and GADD45B as Novel Biomarkers Associated with Chromatin Regulators in Renal Ischemia-Reperfusion Injury

“…Primaquine is an antimicrobial used for the treatment of malaria and pneumocystis jiroveci. While our finding that primaquine may protect against renal IRI appears counterintuitive, as this drug is known to induce oxidative stress, it remains possible that its beneficial effects may derive from its anti-inflammatory actions [84]. Pimozide is a diphenylbutylpiperidine that can be used to treat schizophrenia, Tourette's syndrome, and recurrent tic [85].…”

Artesunate Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Leukocyte Migration to the Central Nervous System

“…Many drugs that were used in the treatment of infections have discovered new uses in the amelioration of inflammation, which is the case of chloroquine, primaquine, dihydroxyartemisinin, and artesunate, among others [19][20][21][22][23][24]. Artesunate (Art), a semi-synthetic sesquiterpene derived from Artemisia annua L., has originally been used in the treatment of malaria [25,26].…”