Background Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1β and IL-18, and induction of cell death (pyroptosis). Among inflammasome family members, the nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) is the most extensively studied and its activation is induced following TBI. As a novel target, drug development targeting the formation and activation of NLRP3 inflammasome is a prospective therapy for TBI. We have recently developed a small molecule JC124 with specificity on NLRP3 inflammasome. In this study, we explored the therapeutic value of JC124 for TBI treatment. Methods Adult male Sprague-Dawley rats were subjected to a moderate cortical impact injury. Following TBI, animals received 4 doses of JC124 treatment with the first dose starting at 30 min, the second dose at 6 h after TBI, the third and fourth doses at 24 or 30 h following TBI, respectively. Animals were sacrificed at 2 days post-injury. Brain tissues were processed either for ELISA and western blotting analysis for inflammatory response, or for histological examination to assess degenerative neurons, acute inflammatory cell response and lesion volume. Results We found that post-injury treatment with JC124 significantly decreased the number of injury-induced degenerating neurons, inflammatory cell response in the injured brain, and cortical lesion volume. Injured animals treated with JC124 also had significantly reduced protein expression levels of NLRP3, ASC, IL-1 beta, TNFα, iNOS, and caspase-1. Conclusion Our data suggest that our novel NLRP3 inhibitor has a specific anti-inflammatory effect to protect the injured brain following TBI.
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD. Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, has shown therapeutic efficacy in a transgenic animal model of AD. In this study we will test the preventative efficacy of JC124 in another strain of transgenic AD mice. Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed. Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions. Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD.
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