Aloe-emodin from Sanhua Decoction inhibits neuroinflammation by regulating microglia polarization after subarachnoid hemorrhage

Abstract

Ethnopharmacological relevance: Subarachnoid hemorrhage (SAH) triggers a cascade of events that lead to early brain injury (EBI), which contributes to poor outcomes and appears within 3 days after SAH initiation. EBI involves multiple process including neuronal death, blood-brain barrier (BBB) injury and inflammation response. Microglia are cluster of immune cells originating in the brain which respond to SAH by changing their states and releasing inflammatory molecules through various signaling pathways. M0, M1, M2 are three states of microglia represent resting state, promoting inflammation state, and anti-inflammation state respectively, which can be modulated by pharmacological strategies.

Aim of the study: After identified potential active ingredients and targets of Sanhua Decoction (SHD) for SAH, we selected aloe-emodin (AE) as a potential ingredient modulating microglia activation states.

Materials and methods: Molecular mechanisms, targets and pathways of SHD were reveal by network pharmacology technique. The effects of AE on SAH were evaluated in vivo by assessing neurological deficits, neuronal apoptosis and BBB integrity in a mouse SAH model. Furthermore, BV-2 cells were used to examine the effects of AE on microglial polarization. The influence of AE on microglia transformation was measured by Iba-1, TNF-α, CD68, Arg-1 and CD206 staining. The signal pathways of neuronal apoptosis and microglia polarization was measured by Western blot.

Results: Network pharmacology identified potential active ingredients and targets of SHD for SAH. And AE is one of the active ingredients. We also confirmed that AE via NF-κB and PKA/CREB pathway inhibited the microglia activation and promoted transformation from M1 phenotype to M2 at EBI stage after SAH.

Conclusions: AE, as one ingredient of SHD, can alleviate the inflammatory response and protecting neurons from SAH-induced injury. AE has potential value for treating SAH-induced nerve injury and is expected to be applied in clinical practice.

Keywords: Aloe-emodin; Apoptosis; Early brain injury; Microglia; NF-κB; Network pharmacology; Neuroinflammation; PKA/CREB; Sanhua decoction; Subarachnoid hemorrhage.