aconitine and Meningitis--Cryptococcal

Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.. In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7(-/-) mice) blockages of α7 nAChR.. As shown in our in vivo studies, BBB injury was significantly reduced in α7(-/-) mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7(-/-) animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).. Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood-Brain Barrier; Central Nervous System Stimulants; Coinfection; Cryptococcus neoformans; HIV Envelope Protein gp41; HIV Infections; HIV-1; Inflammation; Meningitis, Cryptococcal; Methamphetamine; Mice; Mice, Knockout; NF-kappa B; Nicotinic Antagonists