Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 8, Issue 2, 2009

Welcome to the 2009 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (HOT TOPIC) Vol. 8, June 2009. The topic we have chosen for this volume is the treatment of HIV-infection, antiretroviral as well as anti-inflammatory and dopaminergic. We highlight the current therapeutic state-of-the-art as well as future therapeutic options. In particular, Arendt and Nolting analyse the current knowledge on the role of interferons, interleukins, tumor-necrosis factor- alpha, colony-stimulating factors, adhesion molecules and chemokines in neuropathogenesis of HIV-infection and the resulting options for therapeutic procedures. This is important, because it is well-known that antiretroviral therapy alone is not a causative treatment for HIV-related brain disease. Because HIV-patients live longer due to modern antiretroviral therapy, they are endangered of developing virus-related complications as central nervous system disease, so that there is urgent need for adjunctive therapies. Speth and colleagues describe resident immune effector mechanisms in the HIV-infected brain. They emphasize the significance of complement factors and microglia in neuropathogenesis of HIV-infection, especially the diverse antiviral mechanisms exerted by complement and microglia. The authors underline the exploitation of complement to improve cell infection as well as the function of microglia as a viral reservoir and producer of progenitor virus. They present complement and microglia as integral parts of the immune system with positive protective and detrimental abilities in virus infected brains. Eva Neuen-Jacob presents another pathogenetic trait of viral brain infection, i.e., glutamate-mediated neurodysfunction in human (HIV) and simian (SIV) immunodeficieny virus associated encephalitis. From a morphological point of view, she contributes to the glutamate hypothesis for the development of HIV-associated dementia and underlines that the impairment of glutamate clearing plays an important pathogenetic role. Furthermore, she highlights the significance of the N-methyl-Daspartate (NMDA)-receptor activation in the pathogenetic cascades of neurodegenerative disorders including HIV-associated dementia, which thus, is not only an inflammatory, but also a neurodegenerative disorder.

Introduction: HIV-1 is regarded most responsible for a neurodegenerative disease, called HIV-associated dementia (HAD). The pathogenic trait of this severe complication of HIV-infection is still unclear, but disturbed systemic and central nervous system immune function seem to be an important component. Cytokines are important mediators of the human immune system. The review focusses on major cytokines and related immune modulators. Methods: For literature research, the PubMed library, Ovid, Cochrane database, Scirus and Google scholar were used. Results: The article discusses the importance of interferons, interleukins, chemokines, adhesion molecules, colony stimulating factors and tumor necrosis factors. Conclusion: The role of cytokines in the development to HAD is still not clear. Neither their diagnostical or therapeutical potentials nor the basic pathogenetic involvements are completely understood, but the importance of those molecules is evident.

Viral penetration into the central nervous system (CNS) is an early event in the course of human immunodeficiency virus (HIV) pathogenesis and occurs in the vast majority of the infected individuals. Consequences are diverse symptoms of neurological dysfunction in a substantial proportion of patients, as well as the establishment of a lifelong viral reservoir. The severity of symptoms ranges from subclinical alterations in motor and cognitive functions termed HIV neurocognitive impairment (HNCI) to full blown HIV-associated dementia (HAD) in late stages of AIDS. The interaction of HIV with the cerebral immunity is an important aspect of the pathogenesis and has not yet been elucidated in detail. The blood-brain barrier strictly limits the access of peripheral immune elements, thus emphasising the role of the local innate immunity. The two central players of the antimicrobial campaign in the brain are complement and microglia. The complement system represents a fast-acting soluble cascade with a broad variety of antiviral effector mechanisms whereas microglia are the most potent cellular immune elements in the CNS. Both orchestrate a network of innate immune reactions that aim to limit HIV spreading. On the other hand, however, the inflammatory processes may exceed any reasonable limit and develop a dynamic that makes them contribute to the virus-induced neurological damage and dysfunctions. In the present article we describe profit, limitations and danger of the pro-inflammatory activities executed by complement and microglia in the HIV-infected brain. Furthermore we speculate about putative benefits of pro-inflammatory therapies to support the antiviral immune reaction, as well as of anti-inflammatory therapeutic approaches to avoid excessive inflammation and subsequent neurological lesions.

Glutamate-mediated neurodysfunction plays a crucial role in the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) encephalitis. The regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptive changes in the functional elements of the glutamatergic synapse. Our studies in simian immunodeficiency virus (SIV)-infected macaques disclosed disruption of excitatory amino acid transporters (EAATs), the cardinal glutamate clearing system, during SIV infection and a dramatic loss of EAATs associated with development of rapid acquired immunodeficiency syndrome (AIDS) which was paralleled by activated microglia. N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including HIV dementia. The NMDA receptor antagonist memantine is being discussed as a potential adjunctive therapeutic drug for HIV dementia. Interestingly, in the SIV animal model, treatment with memantine during early asymptomatic stage prevented the onset of dopamine deficits in the brains of SIV-infected macaques and specifically up-regulated the brain-derived neurotrophic factor (BDNF). Our data support the glutamate hypothesis for the development of HIV dementia and suggest that the impairment of glutamate clearing plays an important role in the pathogenesis of HIV dementia and SIV encephalitis. Moreover, memantine might be a suitable drug for the treatment of HIV dementia due to its neuroprotective effect.

Pharmacogenomics is a relatively new field in HIV-research, especially when neurological issues are concerned. Influence of polymorphisms in CYP3A4, CYP2B6, CYP2D6, ABCB1, ABCG2, ABCC4, SLC22, SLC28, SLC29 and MMP9-genes on pharmacokinetic data is discussed in the article. Due to the lack of published studies, but promising results in the few existing publications, scientists should be encouraged to integrate neurological aspects in pharmacogenomics research.

Combination antiretroviral therapy (ART) has markedly reduced morbidity and mortality among HIV-infected individuals but not the prevalence of HIV-associated neurocognitive disorders (HAND). Several conditions may be responsible for the high prevalence of cognitive impairment, including incomplete suppression of HIV in nervous system by some antiretrovirals. Since individuals with HAND have a lower quality of life, worse medication adherence, and a higher risk of death, optimizing treatment of neurocognitive outcomes is an important goal of therapy. Optimization of ART to treat the CNS is limited, in part, by the ability of many antiretrovirals to cross the blood-brain barrier (BBB). Differences between antiretrovirals in crossing the BBB - and by extension differences in their concentrations in the brain - may explain inter-individual differences in susceptibility to HAND among treated individuals. This manuscript reviews relevant data on the CSF pharmacology of antiretrovirals and accumulating evidence that the use of drugs that reach therapeutic concentrations in the CNS are the best options to prevent and treat HIV-induced brain injury. Despite the importance of healthy cognition to the quality of patients' lives, consensus treatment guidelines for HAND have yet to be formulated more than two decades after its first description. Formulating widely accepted recommendations for CNS-optimized treatment strategies requires a level of clinical evidence not yet developed but studies are underway to address this shortcoming.

The use of methamphetamine is steadily increasing worldwide. Its use is associated with high-risk sexual behavior and subsequent infection with HIV. Methamphetamine has profound effects on the brain both as an acute intoxicant and following chronic exposure. The combined effects of HIV and methamphetamine appear to result in widespread neuronal and white matter injury. These changes are most prominent in the basal ganglia and frontal lobe, and are not restricted to dopaminergic neurons. Additionally, methamphetamine and HIV proteins disrupt the blood brain barrier, cause glial cell activation and impair the function of neural progenitor cells. Methamphetamine also results in increased HIV replication via activation of chemokine receptors involved in HIV entry. Common pathways in several of these effects seem to involve induction of oxidative stress. Characterization of these subcellular pathways and identification of common targets is essential for development of therapeutic strategies for HIV-infected methamphetamine abusers.

Highly active antiretroviral therapy [HAART] has increased the mean survival time in the AIDS stage by up to more than 10 years. Five different groups of antiretroviral medications are known, of which integrase and entry inhibitors represent the latest and most modern substances. The long survival time in the AIDS stage means that side effects and interactions become of greater relevance and have to be differentiated from the symptoms of Neuro-AIDS as such. Side effects of HAART tend to affect the central and peripheral nervous system as well as the muscles. Neurotoxicity of HAART components varies considerably and depends on the substance involved. They are to be considered with the choice of HAART as a treatment, and a corresponding combination of medication must be carefully discussed by the doctor and patient in those cases in which side effects on the nervous system by antiretroviral agents are already present. There are special cases, however, in which the associated side-effects are to be accepted and endured if no other combination of medications is possible-e.g. as a result of resistance development. Knowledge of HAART side effects and interactions with antiepileptics, antidepressants and analgetics are essential for the treatment of patients with Neuro-AIDS.