Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1

Abstract

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) can lead to cognitive dysfunction, even in individuals treated with highly active antiretroviral therapy. Using an established simian immunodeficiency virus (SIV)/macaque model of HIV CNS disease, we previously reported that infection shifts the balance of activation of mitogen-activated protein kinase (MAPK) signaling pathways in the brain, resulting in increased activation of the neurodegenerative MAPKs p38 and JNK. Minocycline treatment of SIV-infected macaques reduced the incidence and severity of SIV encephalitis in this model, and suppressed the activation of p38 in the brain. The purpose of this study was to further examine the effects of minocycline on neurodegenerative MAPK signaling. We first demonstrated that minocycline also decreases JNK activation in the brain and levels of the inflammatory mediator nitric oxide (NO). We next used NO to activate these MAPK pathways in vitro, and demonstrated that minocycline suppresses p38 and JNK activation by reducing intracellular levels, and hence, activation of apoptosis signal-regulating kinase 1 (ASK1), a MAPKKK capable of selectively activating both pathways. We then demonstrated that ASK1 activation in the brain during SIV infection is suppressed by minocycline. By suppressing p38 and JNK activation pathways, which are important for the production of and responses to inflammatory mediators, minocycline may interrupt the vicious cycle of inflammation that both results from, and promotes, virus replication in SIV and HIV CNS disease.

Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis

“…monocytes and their permissiveness to viral infection. Mechanisms such as decreased p38 activation and viral replication in lymphocytes (Zink et al, 2005), reduced production of MCP-1 altering chemotaxis (Zink et al, 2005), alterations of the pathway activation that regulate viral replication mediated by changes in activation/proliferation markers and cytokine secretion and by inhibition of DNA integration or transcription have been reported (Si et al, 2004;Zink et al, 2005;Follstaedt et al, 2008;Ratai et al, 2010;Szeto et al, 2010). AA is involved in neutrophil function (Wintergerst et al 2006) and can stimulate the production of interferon and other anti-viral cytokines, down regulating inflammation, and viral infection in cultured cells (Bissell et al, 1980;White et al, 1986;Gerber, 1975;Mandl et al, 2009;Mikirova et al, 2012;Furuya et al, 2008).…”

“…This anti-viral effect seems to be linked to its ability to reduce the activation of monocytes and their permissiveness to viral infection. Anti viral mechanisms of MIN include, decreased p38 activation and viral replication in lymphocytes (Zink et al, 2005), reduced production of MCP-1 altering chemotaxis (Zink et al, 2005), blunting changes in activation/proliferation markers and cytokine secretion necessary for the activation pathway that regulate viral replication, decreasing viral production by inhibition of DNA integration or transcription (Si et al, 2004;Zink et al, 2005;Follstaedt et al, 2008;Ratai et al, 2010;Szeto et al, 2010). Several mechanisms of action have been proposed for the potential beneficial effect on viral infections of AA.…”

Minocycline: far beyond an antibiotic

“…Similarly, it has also been shown to reduce virus infection and immune responses in several experimental models (Si et al, 2004;Zink et al, 2005;Follstaedt et al, 2008;Ratai et al, 2010;Szeto et al, 2010). One of the first studies describing this potential use of minocycline in HIV infection was performed in a simian immunodeficiency virus (SIV) macaque model of HIV-associated neurological damage (Zink et al, 2005).…”

HIV-related neurocognitive impairment in the HAART era

“…A clinical trial of minocycline, an antibiotic of the tetracycline class that has neuroprotective and anti-infl ammatory effects, is currently underway. Minocycline was able to suppress SIV encephalitis in an animal model via its inhibition of protein kinases involved in neurodegenerative apoptotic pathways (p38 and JNK) [40].…”