RESUMEN
Progesterone has been shown to exert a wide range of remarkable protective actions in experimental models of central nervous system injury or disease. However, the intimate mechanisms involved in each of these beneficial effects are not fully depicted. In this review, we intend to give the readers a thorough revision on what is known about the participation of diverse receptors and signaling pathways in progesterone-mediated neuroprotective, pro-myelinating and anti-inflammatory outcomes, as well as point out to novel regulatory mechanisms that could open new perspectives in steroid-based therapies.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Progesterona/farmacología , Receptores de Progesterona/metabolismo , Animales , Antiinflamatorios no Esteroideos/química , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Nervioso Central/patología , Humanos , Fármacos Neuroprotectores/química , Progesterona/químicaRESUMEN
Chemotherapy-induced peripheral neuropathy is a disabling condition induced by several frequently used chemotherapeutic drugs including the front-line agent oxaliplatin (OXA). Symptoms are predominantly sensory with the development of neuropathic pain. Alternative dosing protocols and treatment discontinuation are the only available therapeutic strategies. The aim of our work was to evaluate the potential of a synthetic derivative of progesterone, 17α-hydroxyprogesterone caproate (HPGC), in the prevention and treatment of OXA-evoked painful neuropathy. We also evaluated glial activation at the dorsal root ganglia (DRG) and spinal cord levels as a possible target mechanism underlying HPGC actions. Male rats were injected with OXA and HPGC following a prophylactic (HPGCp) or therapeutic (HPGCt) scheme (starting either before or after chemotherapy). The development of hypersensitivity and allodynic pain and the expression of neuronal and glial activation markers were evaluated. When compared to control animals, those receiving OXA showed a significant decrease in paw mechanical and thermal thresholds, with the development of allodynia. Animals treated with HPGCp showed patterns of response similar to those detected in control animals, while those treated with HPGCt showed a suppression of both hypersensitivities after HPGC administration. We also observed a significant increase in the mRNA levels of activating transcription factor 3, the transcription factor (c-fos), glial fibrillary acidic protein, ionized calcium binding adaptor protein 1, interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNFα) in DRG and spinal cord of OXA-injected animals, and significantly lower levels in rats receiving OXA and HPGC. These results show that HPGC administration reduces neuronal and glial activation markers and is able to both prevent and suppress OXA-induced allodynia, suggesting a promising therapeutic strategy.
Asunto(s)
Caproato de 17 alfa-Hidroxiprogesterona/farmacología , Antineoplásicos/farmacología , Hiperalgesia , Neuralgia , Oxaliplatino/farmacología , Enfermedades del Sistema Nervioso Periférico , Progestinas/farmacología , Caproato de 17 alfa-Hidroxiprogesterona/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/prevención & control , Masculino , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/prevención & control , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Progestinas/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. The presence and biological activity of steroidogenic regulatory proteins and enzymes in the spinal cord suggests that neurosteroids locally generated could modulate pain messages. In this study we explored temporal changes in the spinal expression of the 18kDa translocator protein TSPO, the steroidogenic acute regulatory protein (StAr) and the steroidogenic enzyme 5α-reductase (5α-RI/II) in an experimental model of central chronic pain. Male Sprague-Dawley rats were subjected to a SCI and sacrificed at different time points (1, 14 or 28days). The development of mechanical and cold allodynia was assessed. Injured animals showed an early increase in the mRNA levels of TSPO and 5α-RII, whereas in the chronic phase a significant decrease in the expression of 5α-RI and 5α-RII was observed, coinciding with the presence of allodynic behaviors. Furthermore, since we have shown that progesterone (PG) administration may offer a promising perspective in pain modulation, we also evaluated the expression of steroidogenic proteins and enzymes in injured animals receiving daily injections of the steroid. PG-treated did not develop allodynia and showed a marked increase in the mRNA levels of TSPO, StAR, 5α-RI and 5α-RII 28days after injury. Our results suggest that in the acute phase after SCI, the increased expression of TSPO and 5α-RII may represent a protective endogenous response against tissue injury, which is not maintained in the chronic allodynic phase. PG may favor local steroidogenesis and the production of its reduced metabolites, which could contribute to the antiallodynic effects observed after PG treatment.
Asunto(s)
Proteínas Portadoras/metabolismo , Colestenona 5 alfa-Reductasa/metabolismo , Neuralgia/metabolismo , Progesterona/administración & dosificación , Receptores de GABA-A/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Hiperalgesia/enzimología , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Masculino , Neuralgia/enzimología , Neuralgia/etiología , Neuralgia/prevención & control , Umbral del Dolor/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/enzimologíaRESUMEN
Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1ß, its receptors (IL-1RI and IL-1RII) and antagonist (IL-1ra), IL-6 and TNFα, and NR1 subunit of NMDAR. Our results show that progesterone, by modulating the expression of pro-inflammatory cytokines and neuronal IL-1RI/NR1 colocalization, emerges as a promising agent to prevent chronic pain after SCI.