Berberine and palmatine, acting as allosteric potential ligands of α7 <scp>nAChR</scp> , synergistically regulate inflammation and phagocytosis of microglial cells

Berberine and palmatine are isoquinoline quaternary alkaloids derived from Chinese medicinal herbs. These alkaloids have shown promising synergy in inhibiting acetylcholinesterase (AChE), indicating their potential in treating Alzheimer's disease (AD). Besides, the anti-inflammatory effects of berberine and palmatine have been widely reported, although the underlying mechanism remains unclear. Here, we found that berberine and palmatine could induce calcium ion (Ca²⁺) influx via activating α7 nicotinic acetylcholine receptor (α7 nAChR) in cultured microglial cells, possibly serving as its allosteric potential ligands. Furthermore, we examined the synergistic anti-inflammatory effects of berberine and palmatine in the LPS-induced microglia, that significantly suppressed the production of TNF-α and iNOS. Notably, this suppression was reversed by co-treatment with a selective antagonist of α7 nAChR. Moreover, the alkaloid-induced microglial phagocytosis was shown to be mediated by the induction of Ca²⁺ influx through α7 nAChR and subsequent CaMKII-Rac1-dependent pathway. Additionally, the combination of berberine and palmatine, at low concentration, protected against the LPS-induced endoplasmic reticulum stress and mitochondrial dysfunction in microglia. These findings indicate the potential of berberine and palmatine, either individually or in combination, in contributing to anti-AD drug development, which provide valuable insights into the mechanisms by which natural products, such as plant alkaloids, exert their anti-AD effects.