Abstract
Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP). Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions), absorption enhancers (chitosan, papaverine), and mucoadhesive agents (chitosan, polyvinilpyrrolidone) are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV) agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body.
Highlights
Viruses Can Have Important Neurotropic Effects. It is currently well-known that several viruses can have important neurotropic effects in infected bodies: as an example, Canine Distemper Virus (CDV) and Measles Virus (MV) are known to cause demyelinating disease of the central nervous system (CNS) in dogs and humans, respectively; and Eastern Equine Encephalitis Virus (EEEV) is able to induce death or long-lasting and severe neurological sequelae in humans [1]
These data suggest that the conjugation of antiviral drugs with bile acids may constitute a new strategy in order to elude, without inhibiting, the active efflux transporters (AETs) systems that normally preclude the entry of the antiretroviral drugs in Human Immunodeficiency Virus (HIV) sanctuaries
We have evidenced that several viruses can infect the central nervous system, but even if numerous antiviral therapies can be efficacious at peripheral levels, they appear to be inefficacious at the central level, since the antiviral drug substrates of the active efflux transporters (AET) are expressed by the BBB and macrophages
Summary
It is currently well-known that several viruses can have important neurotropic effects in infected bodies: as an example, Canine Distemper Virus (CDV) and Measles Virus (MV) are known to cause demyelinating disease of the central nervous system (CNS) in dogs and humans, respectively; and Eastern Equine Encephalitis Virus (EEEV) is able to induce death or long-lasting and severe neurological sequelae in humans [1]. The lack of penetration of antiretroviral drugs in the HIV sanctuaries is mainly due to the expression of active efflux transporters (AET) on the membranes of lymphocytes [22,23,24], macrophages [25], and the cells that constitute the blood−brain (BBB) and blood−cerebrospinal fluid (BCSFB) barriers [26,27,28]. The antiviral drugs amprenavir, nelfinavir, indinavir (PIs), and abacavir (NRTI) are known as P-gp substrates [43], whereas zidovudine and didanosine appear to be transported by MRP-4 and MRP-5 [32,33,38]. Zidovudine, lamivudine, abacavir, zalcitabine, stavudine, and efavirenz appear as BCRP substrates [44], whereas ritonavir, saquinavir, and nelfinavir are known as inhibitors of this transporter [34]. Zidovudine, didanosine paclitaxel, probenecid, MK-571 zidovudine, lamivudine, abacavir, zalcitabine, stavudine, efavirenz, dolutegravir ritonavir, saquinavir, nelfinavir
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