Progesterone regulates inflammasome expression after spinal cord injury: implications for neuropathic pain

GONZALEZ, SL; RAGGIO MC; CORONEL MF

Buenos Aires

Congreso; LXII Reunión Científica Anual de la Sociedad Argentina de Investigaciones Clínicas.; 2017

Sociedad Argentina de Investigacion Clinica

PROGESTERONE REGULATES INFLAMMASOME EXPRESSION AFTERSPINAL CORD INJURY: IMPLICATIONS FOR NEUROPATHIC PAINAbstract: Neuropathic pain, a frequent complication after spinal cord injury (SCI), isrefractory to available treatment. Spinal glial cell activation and production of proinflammatory mediators, like IL-1β and IL-18, have a critical role in the development of this chronic pain. Neuroinflammatory processes triggered after SCI involve the activation of multiprotein complexes called inflammasomes, containing three main components: NLRP3, ASC and pro-caspase-1. Caspase-1 processes the precursors of IL-1β and IL-18 to its mature forms. We have shown that progesterone (PG), a neuroactive steroid, prevents pain and exerts antiinflammatory actions. To analize whether these effects involve the modulation ofNLRP3 inflammasome, we studied temporal changes in the expression of its components in the acute phase after SCI. Male rats were subjected to spinal hemisection at T13 level and received daily subcutaneous injections of PG (Hx+PG; 16 mg/kg, n=16) or vehicle (HX, n=16). Uninjured rats were used as control (C). Epicenter spinal cord segments were obtained 1 and 3 days post-injury and the mRNA levels of NLPR3, ASC, IL-1β, IL-18 and P2X7 purinergic receptor, involved in inflammasome activation, were determined using RT-PCR. Injured animals showed a significant raise in NLRP3 (p<0.05 vs C) and IL-1β (p<0.001 vs C) mRNA levels 1 day after SCI, as well as a clear increase in P2X7 (p<0.01 vs C), ASC (p<0.001 vs C), NLPR3 (p<0.001 vs C) and IL-18 (p<0.01 vs C) transcripts 3days after injury. At this time point, animals treated with PG showed significantly lower levels of NLPR3 (p<0.01 vs C; p<0.05 vs HX), while P2X7, ASC and IL-18 expression levels remained similar to control values (p>0.05 vs C; p<0.05 vs HX in all cases). These results suggest that PG, by modulating spinal mechanisms associated with NLRP3 inflammasome activation, could stand as a promising therapeutic alternative for SCI-induced neuropathic pain (PIP CONICET 266, Fundación Barón, Fundación Williams).Keywords: Progesterone, inflammasome, chronic pain