Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Abstract

Recent studies have demonstrated a close interaction between neuroinflammatory responses, increased production of inflammatory mediators, and neurodegeneration. Pathological findings in neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease have shown common signs of neuroinflammation and neurodegeneration. Lupeol, a natural pentacyclic triterpene, has revealed a number of pharmacological properties including an anti-inflammatory activity. This study aimed to evaluate the effect of lupeol against lipopolysaccharide (LPS)-induced neuroinflammation in the cortex and hippocampus of adult mice. Our results showed that systemic administration of LPS induced glial cell production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1β, while co-treatment with lupeol significantly inhibited the LPS-induced activation of microglia and astrocytes, and decreased the LPS-induced generation of TNF-α, iNOS, and IL-1β. The intracellular mechanism involved in the LPS-induced activation of inflammatory responses includes phosphorylation of P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which was significantly inhibited by lupeol. We further elucidated that lupeol inhibited the LPS-induced activation of the mitochondrial apoptotic pathway and reversed the LPS-induced expression of apoptotic markers such as Bax, cytochrome C, caspase-9, and caspase-3. Taken together; our results suggest that lupeol inhibits LPS-induced microglial neuroinflammation via the P38-MAPK and JNK pathways and has therapeutic potential to treat various neuroinflammatory disorders.

Lupeol Isolated from Betula alnoides Ameliorates Amyloid Beta Induced Neuronal Damage via Targeting Various Pathological Events and Alteration in Neurotransmitter Levels in Rat’s Brain

“…which stay in good agreement with its previous findings [51]. However, lupeol treatment significantly attenuated Aβ induced oxidative-nitritive stress and decreased the levels of pro-inflammatory cytokines, confirming its antioxidant and antiinflammatory properties [52].…”

Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway

“…Systemic administration of LPS evokes inflammatory processes in the body, which cause detrimental effects on the brain and other vital organs. In vitro and in vivo studies demonstrated that LPS induced inflammation via the up-regulation of different proinflammatory mediators, such as nitric oxide species (NOS), prostaglandin E2 (PGE2), and cyclooxygenase (COX)-2, and proinflammatory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) 1 2 3 .…”

“…Toll-like receptors (TLRs) play important roles in the sensing of body pathogens and macrophages and the initiation of immune responses. LPS is primarily recognized by the CD14/TLR-4 receptor complex, which is expressed on microglia and astrocytes in the CNS 1 4 5 . The downstream signal transduction of this receptor complex activates the TLR4/nuclear factor (NF)-κB pathway, which leads to the generation of inflammatory mediators and the production of neuroinflammation and neurodegeneration 6 7 .…”

Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor α in a β-amyloid protein -dependent mechanism

“…In agreement with our observations, accumulating evidence indicates that the p38 and JNK/c-Jun pathways are involved in the regulation of the expression of TNF-α. However, although investigators tried to identify the mechanisms responsible for the suppression of the expression of TNF-α in astrocyte, this work did not extend to PGE 2 and PGI 2 [ 50 - 54 ]. This is not the first time we have demonstrated the involvement of the p38 and JNK/c-Jun pathways in regulating the expression of TNF-α; however, we extended these mechanisms to include the roles of PGE 2 and PGI 2 in regulating the synthesis of TNF-α.…”