Improved Promotion of M2 Microglial Polarization by Zuogui Jiangtang Jieyu Formulation in Diabetes-Related Depression

Abstract Background Zuogui Jiangtang Jieyu formulation (ZGJTJY) is a Chinese polyherbal prescription for diabetes-related depression (DD). The mechanism underlying hippocampal M1/M2 polarization in DD and the ZGJTJY treatment effects remain unclear. This study aimed to investigate M1/M2 microglial polarization in the hippocampus of DD rats and HAPI (highly aggressively proliferating immortalized) cells simulating the DD state, as well as to examine the ZGJTJY intervention effects, both in vivo and in vitro. Methods We subjected Sprague Dawley rats to a high-fat diet, streptozotocin, and unpredictable chronic mild stress; subsequently, we orally administered ZGJTJY. HAPI cells were induced using high glucose and corticosterone; subsequently, ZGJTJY-containing serum was added to examine changes in M1/M2 microglial polarization. Moreover, metformin combined with fluoxetine (DMGB/F) was used as a positive drug for evaluating the ZGJTJY intervention. Laser confocal scanning was used to examine the microglial morphology. Further, real-time PCR was used to determine M1 markers (MHCII, iNOS, MCP-1, CD11b), M2 markers (Arg1, Mrc1, Ym1), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and anti-inflammatory cytokines (IL-4, IL-10). Additionally, an enzyme-linked immunosorbent assay was used to examine inflammatory cytokines. Results There was significant activation of M1 polarization in the hippocampus of DD rats and HAPI cells induced using high glucose and corticosterone. Compared with DMGB/F, ZGJTJY inhibited and promoted M1 and M2 polarization, respectively; moreover, it decreased the M1-to-M2 polarization ratio both in vivo and in vitro. Conclusions The study indicated that hippocampal M1 polarization is crucially involved in DD pathogenesis; moreover, there is a need for further research on the neuroprotective effect of Chinese medicine associated with M2-polarized microglia.