About this Research Topic
Several anti-viral agents have been associated with a wide range of neurotoxic effects, from peripheral neuropathy to central nervous system (CNS) deficits, such as neurocognitive impairment and neuropsychiatric symptoms. A well-known example is represented by the class of anti-retroviral agents, mainly used to treat anti-human immunodeficiency virus (HIV) infections. Although the combination anti-retroviral therapy (cART) has strongly reduced the incidence and severity of HIV-associated neurocognitive disorders (HANDs), due to the suppression of viral replication, several patients still manifest a certain degree of neuropsychological consequences that can be related to the therapy itself. The most remarkable example among those drugs is efavirenz, a widely used non-nucleoside reverse transcriptase inhibitor (NNRTI), that has been strongly associated with neurocognitive impairment and psychiatric adverse effects. Apart from anti-HIV drugs, further anti-viral molecules have demonstrated neurotoxic effects, such as acyclovir, valcyclovir or ganciclovir, widely used in the treatment of varicella-zooster virus (VZV), herpes simplex virus (HSV) and cytomegalovirus (CMV), but also type I interferon (IFN-I), extensively used for hepatitis C virus (HCV) infection.
Several mechanisms of cART neurotoxicity have been proposed. Direct neuronal toxicity derived from the induction of the unfolded protein response, loss of membrane integrity, and the release of calcium or mitochondrial dysfunctions with oxidative stress and apoptosis has been observed in in vivo and in vitro models. Other mechanisms include amyloidogenic effects, dysfunctions of the blood-brain barrier (BBB), impaired myelination, and interference with neurotransmitters.
Regarding anti-viral molecules such as the nucleoside analogs acyclovir and its derivative valcyclovir, a proposed mechanism of neurotoxicity is the off-target inhibition of mitochondrial DNA polymerase, with consequent mitochondrial toxicity and oxidative stress, similar to the side-effects of several nucleoside reverse transcriptase inhibitors (NRTIs) used for HIV infection therapy. As regards IFN-I neurotoxicity, there are different mechanisms, most probably mediated by the activation of signaling cascades associated with the interferon receptor (IFNAR), the modulation of glutamate levels, the interference with synaptic transmission and membrane potential, and the upregulation of inflammatory cytokines.
Moreover, some anti-viral drugs have been associated with neurodevelopmental defects or more subtle changes in cognitive functions or social and emotional behavior later in life, after perinatal exposure. For these reasons, their use during pregnancy has been methodically/systematically discussed by clinicians. This is the case, for example, of dolutegravir, an HIV integrase inhibitor, associated with the increase in the risk of neural tube defects.
The evaluation of developmental safety and efficacy of therapeutic drugs during pregnancy is hampered by the under-representation of females of childbearing potential and the exclusion of pregnant women from registrational drug trials.
There is still an urgent need to study the neurotoxicity and neurodevelopmental effects of anti-viral drugs, in particular for anti-HIV drugs, considering the high number of infected females of childbearing age worldwide. Together with human patient data, several in vivo and in vitro models have been used systematically to conduct controlled investigations of anti-viral neurotoxicity and neurodevelopmental effects, from classical animal models (rodents, rabbits, and zebrafish) to advanced cell models (human IPSC, 2D and 3D cell cultures).
The aim of this Research Topic is to provide an updated overview of the neurotoxic and neurodevelopmental effects caused by anti-viral drugs. To do this we welcome clinical and pre-clinical research-focused contributions addressing, but not limited to, the following:
- molecular mechanisms of neurotoxicity and neurodevelopmental effects of anti-viral drugs
- approaches, models, and tools (in vivo, in vitro, in silicon) to explore neurotoxicity and neurodevelopmental effects of anti-viral drugs
- epidemiological/clinical studies focused on neurotoxic and neurodevelopmental effects of anti-viral drugs
- clinical information about cases with neurological/neuropsychiatric adverse events following the use of anti-viral drugs.
Several mechanisms of cART neurotoxicity have been proposed. Direct neuronal toxicity derived from the induction of the unfolded protein response, loss of membrane integrity, and the release of calcium or mitochondrial dysfunctions with oxidative stress and apoptosis has been observed in in vivo and in vitro models. Other mechanisms include amyloidogenic effects, dysfunctions of the blood-brain barrier (BBB), impaired myelination, and interference with neurotransmitters.
Regarding anti-viral molecules such as the nucleoside analogs acyclovir and its derivative valcyclovir, a proposed mechanism of neurotoxicity is the off-target inhibition of mitochondrial DNA polymerase, with consequent mitochondrial toxicity and oxidative stress, similar to the side-effects of several nucleoside reverse transcriptase inhibitors (NRTIs) used for HIV infection therapy. As regards IFN-I neurotoxicity, there are different mechanisms, most probably mediated by the activation of signaling cascades associated with the interferon receptor (IFNAR), the modulation of glutamate levels, the interference with synaptic transmission and membrane potential, and the upregulation of inflammatory cytokines.
Moreover, some anti-viral drugs have been associated with neurodevelopmental defects or more subtle changes in cognitive functions or social and emotional behavior later in life, after perinatal exposure. For these reasons, their use during pregnancy has been methodically/systematically discussed by clinicians. This is the case, for example, of dolutegravir, an HIV integrase inhibitor, associated with the increase in the risk of neural tube defects.
The evaluation of developmental safety and efficacy of therapeutic drugs during pregnancy is hampered by the under-representation of females of childbearing potential and the exclusion of pregnant women from registrational drug trials.
There is still an urgent need to study the neurotoxicity and neurodevelopmental effects of anti-viral drugs, in particular for anti-HIV drugs, considering the high number of infected females of childbearing age worldwide. Together with human patient data, several in vivo and in vitro models have been used systematically to conduct controlled investigations of anti-viral neurotoxicity and neurodevelopmental effects, from classical animal models (rodents, rabbits, and zebrafish) to advanced cell models (human IPSC, 2D and 3D cell cultures).
The aim of this Research Topic is to provide an updated overview of the neurotoxic and neurodevelopmental effects caused by anti-viral drugs. To do this we welcome clinical and pre-clinical research-focused contributions addressing, but not limited to, the following:
- molecular mechanisms of neurotoxicity and neurodevelopmental effects of anti-viral drugs
- approaches, models, and tools (in vivo, in vitro, in silicon) to explore neurotoxicity and neurodevelopmental effects of anti-viral drugs
- epidemiological/clinical studies focused on neurotoxic and neurodevelopmental effects of anti-viral drugs
- clinical information about cases with neurological/neuropsychiatric adverse events following the use of anti-viral drugs.
Keywords: anti-viral drugs, anti-retroviral therapy (cART), neurotoxicity, neurodevelopmental toxicity, neuropsychiatric adverse events
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