Pharmacology seminars

Las enfermedades neurodegenerativas como la Enfermedad de Alzheimer, Enfermedad de Parkinson y la Esclerosis Lateral Amiotrófica tienen una prevalencia creciente en nuestra sociedad, de acuerdo con el aumento de la expectativa de vida. Durante el envejecimiento, las células gliales sufren cambios funcionales favoreciendo la “neuroinflamación”, que tiene un reconocido papel patogénico en la progresión de la enfermedad neurodegenerativa. Estudios recientes demuestran que durante el envejecimiento del sistema nervioso se acumulan notablemente células senescentes, tanto de estirpe neuronal como glial. Las células senescentes no proliferan, muchas de ellas exhiben un fenotipo secretor (SASP) con capacidad de inducir inflamación. La eliminación de células senescentes por ablación genética inducida farmacológicamente o por bloqueos de fármacos senolíticos mejoran la neuroinflamación y disminuyen la neurotoxicidad. En la presentación, se realizará una revisión de la bibliografía sobre este tema y se realizará un análisis del potencial terapéutico de fármacos senolíticos como una aproximación terapéutica novedosa de las enfermedades neurodegenerativas.

After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow during embryonic development and after an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. This study has uncovered a previously unknown role for SGC in nerve regeneration and defined SGC as transcriptionally distinct from Schwann cells while sharing similarities with astrocytes. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Through repurposing fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, we were able to rescue the impaired regeneration in mice lacking Fasn in SGC. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.

Behavioral states such as arousal and attention can have profound effects on sensory processing, determining how – sometimes whether – a stimulus is processed. This state-dependence is believed to arise, at least in part, as a result of inputs to cortex from subcortical structures that release neuromodulators such as acetylcholine, noradrenaline, and serotonin, often non-synaptically. The mechanisms that underlie the interaction between these “wireless” non-synaptic signals and the “wired” cortical circuit are not well understood. Furthermore, neuromodulatory signaling is traditionally considered broad in its impact across cortex (within a species) and consistent in its form and function across species (at least in mammals). The work I will present approaches the challenge of understanding neuromodulatory action in the cortex from a number of angles: anatomy, physiology, pharmacology, and chemistry. The overarching goal of our effort is to elucidate the mechanisms behind local neuromodulation in the cortex of non-human primates, and to reveal differences in structure and function across cortical model systems.

Chemotherapeutic drugs (used for treating cancer), HIV infection and antiretroviral therapy (ART) can independently cause difficult-to-manage painful neuropathy. Paclitaxel, a chemotherapeutic drug, for example is associated with high incidence of peripheral neuropathy, around 71% of the patients of which 27% of these develop neuropathic pain. Use of cannabis or phytocannabinoids has been reported to improve pain measures in patients with neuropathic pain, including painful HIV-associated sensory neuropathy and cancer pain. Phytocannabinoids and endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), produce their effects via cannabinoid (CB) receptors, which are present both in the periphery and central nervous system. Endocannabinoids are synthesized in an “on demand” fashion and are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Various studies, including those from our group, suggest that there are changes in gene and protein expression of endocannabinoid molecules during chemotherapy-induced neuropathic pain (CINP), HIV and antiretroviral-induced neuropathic pain. Analysis of endocannabinoid molecule expression in the brain, spinal cord and paw skin using LC-MS/MS show that there is a specific deficiency of the endocannabinoids 2-AG and/or anandamide in the periphery during CINP. Various drugs including endocannabinoids, cannabidiol, inhibitors of FAAH and MGL, CB receptor agonists, desipramine and coadministered indomethacin plus minocycline have been found to either prevent the development and/or attenuate established CINP, HIV and antiretroviral-induced neuropathic pain in a CB receptor-dependent manner. The results available suggest that targeting the endocannabinoid system for prevention and treatment of CINP, HIV-associated neuropathic pain and antiretroviral-induced neuropathic pain is a plausible therapeutic option.