The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury

Although the precise mechanisms contributing to secondary brain injury following traumatic brain injury are complex and obscure,a number of studies have demonstrated that inflammatory responses are an obvious and early feature in the pathogenesis of traumatic brain injury.Inflammasomes are multiprotein complexes that prompt the stimulation of caspase-1 and subsequently induce the maturation and secretion of proinflammatory cytokines,such as interleukin-1β and interleukin-18.These cytokines play a pivotal role in facilitating innate immune responses and inflammation.Among various inflammasome complexes,the NOD-like receptor family pyrin domain-containing 3(NLRP3)inflammasome is the best characterized,a crucial role for NLRP3 has been demonstrated in various brain diseases,including traumatic brain injury.Several recent studies have revealed the contribution of NLRP3 inflammasome in identifying cellular damage and stimulating inflammatory responses to aseptic tissue injury after traumatic brain injury.Even more important,blocking or inhibiting the activation of the NLRP3 inflammasome may have substantial potential to salvage tissue damage during traumatic brain injury.In this review,we summarize recently described mechanisms that are involved in the activation and regulation of the NLRP3 inflammasome.Moreover,we review the recent investigations on the contribution of the NLRP3 inflammasome in the pathophysiology of TBI,and current advances and challenges in potential NLRP3-targeted therapies.A significant contribution of NLRP3 inflammasome activation to traumatic brain injury implies that therapeutic approaches focused on targeting specific inflammasome components could significantly improve the traumatic brain injury outcomes.

Thioredoxin interacting protein,a key molecular switch between oxidative stress and sterile inflammation in cellular response

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

Verapamil,a possible repurposed therapeutic candidate for stroke under hyperglycemia

Admission hyperglycemia is an independent predictor,that contributes to hemorrhagic transformation (HT),and worsened functional outcome following reperfusion therapy with tissue plasminogen activator (tPA) in ischemic stroke.Clinical studies have revealed a strong association between hyperglycemia and incidence of HT independent of prior diabetes diagnosis (Alvarez-Sabin et al.