ABSTRACT
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Subject(s)
Anti-Infective Agents, Local/pharmacology , Drug Evaluation, Preclinical/methods , Sexually Transmitted Diseases, Bacterial/prevention & control , Sexually Transmitted Diseases, Viral/prevention & control , Administration, Intravaginal , Administration, Rectal , Animals , Anti-Infective Agents, Local/chemistry , Anti-Infective Agents, Local/classification , Anti-Infective Agents, Local/isolation & purification , Anti-Infective Agents, Local/toxicity , Clinical Trials as Topic , Disease Models, Animal , Drug Approval , Enzyme Inhibitors/pharmacology , Female , HIV Infections/prevention & control , HIV Infections/transmission , Herpes Genitalis/prevention & control , Herpes Genitalis/transmission , Humans , Male , Multicenter Studies as Topic , Papillomavirus Infections/prevention & control , Papillomavirus Infections/transmission , Surface-Active Agents/pharmacology , Technology, Pharmaceutical/methods , Viral Proteins/antagonists & inhibitors , Virus Internalization/drug effectsABSTRACT
Los microbicidas constituyen una nueva herramienta, todavía en proceso de investigación, que podrían ayudar en la prevención de la infección por los virus de la inmunodeficiencia humana (Human immunodeficiency virus: HIV) y de otras infecciones de transmisión sexual (ITS). Una serie de evidencias ha demostrado que la complejidad de la transmisión sexual de patógenos virales requiere de la identificación de compuestos capaces de bloquear los eventos tempranos del ciclo de infección viral. En este manuscrito hacemos una revisión exhaustiva de las diferentes estrategias que se han estudiado o se están considerando para prevenir ITS mediante el uso de microbicidas, haciendo particular énfasis en aquellos con el potencial de bloquear la infección por el HIV. También se revisa el proceso complejo de evaluación preclínica que se requiere para llegar a estudios en humanos y se concluye con un breve análisis de las estrategias que podrían formar parte del futuro inmediato en la investigación de microbicidas
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research
Subject(s)
Sexually Transmitted Diseases/prevention & control , Anti-HIV Agents/analysis , Papillomavirus Vaccines/analysis , Antiviral Agents/therapeutic use , Sexually Transmitted Diseases/diagnosis , Sexually Transmitted Diseases/therapy , Herpesvirus 2, Human/drug effects , Anti-Infective Agents/therapeutic useABSTRACT
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Subject(s)
Anti-Infective Agents, Local/pharmacology , Drug Evaluation, Preclinical/methods , Sexually Transmitted Diseases, Bacterial/prevention & control , Sexually Transmitted Diseases, Viral/prevention & control , Administration, Intravaginal , Administration, Rectal , Animals , Anti-Infective Agents, Local/chemistry , Anti-Infective Agents, Local/classification , Anti-Infective Agents, Local/isolation & purification , Anti-Infective Agents, Local/toxicity , Clinical Trials as Topic , Disease Models, Animal , Drug Approval , Enzyme Inhibitors/pharmacology , Female , HIV Infections/prevention & control , HIV Infections/transmission , Herpes Genitalis/prevention & control , Herpes Genitalis/transmission , Humans , Male , Multicenter Studies as Topic , Papillomavirus Infections/prevention & control , Papillomavirus Infections/transmission , Surface-Active Agents/pharmacology , Technology, Pharmaceutical/methods , Viral Proteins/antagonists & inhibitors , Virus Internalization/drug effectsABSTRACT
Cyclin-dependent kinase 5/p35 kinase complex plays a critical role in dopaminergic neurotransmission. Dysregulation of dopamine (DA) signaling is associated with neurological and neuropsychiatric disorders. As cyclin-dependent kinase 5 (Cdk5) requires association with p35 for its proper activation, we hypothesized that dysregulation of Cdk5 activity might have an effect on striatal-mediated behavior. We used a mutant mouse, deficient in p35 protein (p35 KO), which displayed reduced Cdk5 activity. Throughout behavioral and biochemical characterization of naïve and psychostimulant-treated mice, we demonstrated that only juvenile p35 KO mice displayed spontaneous hyperactivity, responded with a paradoxical hypolocomotor effect to psychostimulant drugs and exhibited deficit on proper behavioral inhibition. Strong immunolabeling for tyrosine-hydroxylase and high striatal DA synthesis and contents with a low DA turnover, which were reverted by psychostimulants, were also found in mutant mice. Our results demonstrate that p35 deficiency is critically involved in the expression of a hyperactive behavioral phenotype with hyper-functioning of the dopaminergic system, emphasizing the importance of proper Cdk5 kinase activity for normal motor and emotional features. Thus, p35 KO mice may be another useful animal model for understanding cellular and molecular events underlying attention deficit hyperactivity disorder-like disorders.
Subject(s)
Central Nervous System Stimulants/pharmacology , Cyclin-Dependent Kinase 5/physiology , Hyperkinesis/psychology , Motor Activity/drug effects , Nerve Tissue Proteins/physiology , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Cyclin-Dependent Kinase 5/genetics , Dextroamphetamine/pharmacology , Disease Models, Animal , Dopamine/metabolism , Hyperkinesis/genetics , Inhibition, Psychological , Male , Maze Learning/drug effects , Methylphenidate/pharmacology , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Stress exposure induces long lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. In the present study, previously restrained animals exhibited excessive anxiety one day later in the elevated plus maze. We explore whether stress exposure affects the expression levels of cyclin-dependent kinase 5 (Cdk5) and of its activator protein p35, in diverse amygdaloid nuclei. Stress exposure enhanced p35 levels selectively in the basolateral amygdala (BLA). This up-regulation might be functionally associated with the occurrence of exaggerated anxiety since such emotional response was selectively reversed by an intra-BLA infusion of olomoucine, a Cdk5 inhibitor, 15 min prior to the restraint session. Moreover, pre-treatment with midazolam, a benzodiazepine ligand, not only prevented the excessive anxiety but also attenuated the p35 increase in the BLA of stressed rats. In conclusion, we suggest a pivotal role of the Cdk5/p35 complex, specifically in BLA in the excessive anxiety induced by a previous stressful experience.
Subject(s)
Amygdala/metabolism , Anti-Anxiety Agents/pharmacology , Anxiety/psychology , Behavior, Animal/drug effects , Interleukin-12 Subunit p35/metabolism , Midazolam/pharmacology , Stress, Psychological/psychology , Amygdala/anatomy & histology , Amygdala/drug effects , Animals , Cell Count , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Cyclin-Dependent Kinase 5/metabolism , Enzyme Inhibitors/pharmacology , Immunohistochemistry , Interleukin-12 Subunit p35/antagonists & inhibitors , Kinetin/pharmacology , Male , Rats , Rats, Wistar , Restraint, Physical , Up-Regulation/drug effectsABSTRACT
The cellular and molecular mechanisms of sensitization in the addictive process are still unclear. Recently, chronic treatment with cocaine has been shown to upregulate the expression of cyclin-dependent kinase 5 (cdk5) and its specific activator, p35, in the striatum, as a downstream target gene of DeltaFosB, and has been implicated in compensatory adaptive changes associated with psychostimulants. Cdk5 is a serine/threonine kinase and its activation is achieved through association with a regulatory subunit, either p35 or p39. P35 is cleaved by the protease calpain, which results in the generation of a truncated product termed p25, which contains all elements necessary for cdk5 activation. The cdk5/p35 complex plays an essential role in neuronal development and survival. It has also been involved in neuronal trafficking and transport and in dopaminergic transmission, indicating its role either in presynaptic and postsynaptic signaling. In this study we report that the cdk5/p35 complex participates in acute and chronic d-amphetamine (AMPH)-evoked behavioral events, and we show a surprisingly transient enhanced expression of p25 and a lasting increased expression of p35 in dorsal striatal synaptosomes after acute and chronic AMPH administration. Pak1, a substrate for cdk5, is also enriched in the synaptosomal fraction of acute AMPH-treated rats. Our data suggest that the transient upregulation of p25 may regulate the activity of cdk5 in phosphorylating particular substrates, such as Pak1, implicated in the compensatory adaptive morphophysiologic changes associated with the process of behavioral sensitization to psychostimulants.