Targeting Pro-Inflammatory Interleukin-1 Beta Signaling to Modulate Neuroinflammatory Processes Associated with Cognitive Decline in Dementia with Lewy Bodies

Abstract

Highlights What are the main findings? The oral p38α kinase inhibitor neflamapimod potently (EC50 ~6 nM) inhibits IL-1β-induced IL-6 and IL-8 production from human peripheral blood mononuclear cells. In clinical studies, neflamapimod reduces CSF levels of IL-6 and IL-8 in patients with early Alzheimer’s disease, and in patients with dementia with Lewy bodies (DLB) increases the β-amyloid peptide 1–42 to 1–40 (Aβ42/40) ratio in plasma, while reducing plasma glial fibrillary acidic protein (GFAP) levels. What is the implication of the main finding? Neflamapimod demonstrated potent inhibition of pro-inflammatory IL-1β signaling in vitro at clinically relevant drug concentrations. The associated effects on CSF cytokines, plasma Aβ42/40 ratio, and plasma GFAP in clinical studies support the hypothesis that inhibition of p38α-dependent IL-1β signaling beneficially modulates neuroinflammatory processes underlying cognitive decline in DLB, and potentially in AD. Abstract Interleukin-1 beta (IL-1β) is implicated as a molecular driver of cognitive decline in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), potentially through activation of pro-inflammatory pathways within the neuron that impair synaptic function. Because pro-inflammatory IL-1β signaling depends on p38α kinase, the oral brain-penetrant p38α inhibitor neflamapimod has the potential to reverse synaptic dysfunction and treat cognitive decline in these contexts. Neflamapimod has also shown positive effects in animal models and in clinical studies in AD and DLB. Herein we evaluated neflamapimod effects on pro-inflammatory IL-1β signaling in vitro and in patients with AD or DLB. In human PBMCs, neflamapimod inhibited IL-1β-induced IL-6 and IL-8 production with EC50 values of 6.3 ± 1.3 nM and 7.1 ± 3.2 nM, respectively. In AD, six weeks of neflamapimod 40 mg BID treatment reduced CSF levels of IL-6 and IL-8, with maximal effects at trough drug concentration ≥4 ng/mL (9 nM). In DLB, neflamapimod 40 mg TID increased the plasma Aβ42/40 ratio and reduced plasma GFAP levels, treatment effects consistent with reduced pro-inflammatory IL-1β signaling. Collectively, these results support the hypothesis that inhibition of p38α-dependent IL-1β signaling may beneficially modulate neuroinflammatory processes that otherwise are associated with cognitive decline in DLB, and potentially in AD.