The Implications of Brain-Derived Neurotrophic Factor in the Biological Activities of Platelet-Rich Plasma.

Platelet-rich plasma (PRP) is a biological blood-derived therapeutic obtained from whole blood that contains higher levels of platelets. PRP has been primarily used to mitigate joint degeneration and chronic pain in osteoarthritis (OA). This clinical applicability is based mechanistically on the release of several proteins by platelets that can restore joint homeostasis. Platelets are the primary source of brain-derived neurotrophic factor (BDNF) outside the central nervous system. Interestingly, BDNF and PRP share key biological activities with clinical applicability for OA management, such as anti-inflammatory, anti-apoptotic, and antioxidant. However, the role of BDNF in PRP therapeutic activities is still unknown. Thus, this work aimed to investigate the implications of BDNF in therapeutic outcomes provided by PRP therapy in vitro and in-vivo, using the MIA-OA animal model in male Wistar rats. Initially, the PRP was characterized, obtaining a leukocyte-poor-platelet-rich plasma (LP-PRP). Our assays indicated that platelets activated by Calcium release BDNF, and suppression of M1 macrophage polarization induced by LP-PRP depends on BDNF full-length receptor, Tropomyosin Kinase-B (TrkB). OA animals were given LP-PRP intra-articular and showed functional recovery in gait, joint pain, inflammation, and tissue damage caused by MIA. Immunohistochemistry for activating transcriptional factor-3 (ATF-3) on L4/L5 dorsal root ganglia showed the LP-PRP decreased the nerve injury induced by MIA. All these LP-PRP therapeutic activities were reversed in the presence of TrkB receptor antagonist. Our results suggest that the therapeutic effects of LP-PRP in alleviating OA symptoms in rats depend on BDNF/TrkB activity.

Intraarticular monomethyl fumarate as a perspective therapy for osteoarthritis by macrophage polarization.

BACKGROUND: Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF). RESULTS: DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase). CONCLUSIONS: Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.