Balasubramide derivative 3C modulates microglia activation via CaMKKβ-dependent AMPK/PGC-1α pathway in neuroinflammatory conditions

Involvement of AMP‐activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain

“…Also, AMPK/Nrf2 signaling is involved in anti‐inflammatory action of Petatewalide B against LPS in microglia (Park et al, 2018). Similar to the results shown in microglial culture, LPS decreases p‐AMPK levels (Zhou et al, 2014), and AMPK activation by various activators suppresses pro‐inflammatory reactions and enhances anti‐inflammatory reactions in LPS‐induced rodent neuroinflammation models (Lu et al, 2010; Wang et al, 2018d; Xu et al, 2015; Zhou et al, 2014; Li et al, 2018a). For instance, while LPS [intracerebroventricular (icv) injection] decreases p‐AMPK levels and induces expression of M1 signature genes (iNOS, IL‐1β, TNFα, and IL‐6) in the lateral septal complex area, administration of hydrogen sulfide (H2S) donors enhances AMPK activation, attenuates M1 signature gene expression, and enhances expression of M2 signature genes (Arg‐1, YM1/2, and IL‐10) (Zhou et al, 2014).…”

“…Accumulating data from experiments using LPS as a trigger for pro‐inflammatory reactions indicate that AMPK activation induces a microglial phenotypic shift from pro‐inflammatory to anti‐inflammatory in AMPK activation‐dependent manner. In primary cultured microglia or BV2, LPS‐induced pro‐inflammatory reaction is associated with reduction in phospho (p)‐AMPK (activated AMP) (Li et al, 2018b; Park et al, 2018; Xu et al, 2015; Zhou et al, 2014), and AMPK activators including metformin and 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) suppress pro‐inflammatory and enhance anti‐inflammatory reactions (Giri et al, 2004; Lee et al, 2015; Lu et al, 2010; Li et al, 2018a; Xu et al, 2015; Park et al, 2018; Wang et al, 2018d; Zhou et al, 2014; Velagapudi et al, 2017; Chen et al, 2014). For example, AICAR (an analogue of AMP) attenuates LPS‐induced activation of NF‐κB and inhibits expression of proinflammatory cytokines (TNF‐α, IL1β, IL‐6) and iNOS, and these effects of AICAR are inhibited by the dominant negative form of AMPK and anti‐sense AMPK treatment in primary rat astrocytes, microglia, and peritoneal macrophages (Giri et al, 2004).…”

“…Balasubramide derivative 3C ameliorates depressive behaviors of LPS (i.p. )‐induced neuroinflammatory mice by promoting the anti‐inflammatory activation of microglia through the CaMKKβ‐dependent AMPK/peroxisome proliferator‐activated receptor‐γ coactivator (PGC‐1α) signaling pathway (Wang et al, 2018d). Salvanoic acid C inhibits LPS‐induced inflammatory response and NF‐ĸB activation through the activation of AMPK/Nrf2 signaling in vivo and in vitro (Song et al, 2018).…”

“…Thus, AMPK activation seems to attenuate proinflammatory reaction induced by LPS and enhance anti‐inflammatory reaction both in in vivo and in vitro. Although metformin and other AMPK activators used in these experiments may not be specific to AMPK, experiments using AMPK siRNAs or other inhibitors and genetic modifications of AMPK indicate the importance of AMPK activation in the microglial shift from pro‐ to anti‐inflammatory phenotypes (Giri et al, 2004; Li et al, 2018a; Park et al, 2018; Song et al, 2018; Wang et al, 2018d; Zhou et al, 2014). These experiments also show that LPS treatment decreases microglial p‐AMPK levels, which are restored by AMPK activators.…”

“…Such anti‐inflammatory polarization of microglia induced by AMPK activation is often associated with neuroprotection in animal models of brain disorders, such as ischemic, Parkinson's, and streptozotocin‐induced diabetic models (Jing et al, 2013; Lu et al, 2016; Oliveira et al, 2016; Wang et al, 2018d, c). However, in Parkinson's (MPTP) model, while metformin reduces microglial morphological changes as well as TNF‐α, IL‐1β and iNOS mRNAs levels, it exacerbates dopaminergic neuron damage (Ismaiel et al, 2016).…”