No abstract

Simultaneous relief of the pain from body and brain remains an ongoing challenge. The aim of the present study was to clarify whether plant-derived isoflavone puerarin could ameliorate comorbid depression and pain. We investigated the effects of puerarin on depressive-like behaviors and neuropathic pain in C57BL/6 N mice with spared nerve injury (SNI). After SNI surgery, mice were allowed to recover spontaneously for 7 days and subsequently treated with puerarin, anti-depressant citalopram, and analgesic ibuprofen, alone or in combination, for 8 or 14 days. Forced swim test and tail suspension test were used to assess depressive-like behaviors, whereas von Frey filament test was used to estimate the sensitivity to the mechanical stimulation. Our results suggested that puerarin effectively ameliorated depression and pain in SNI mice although citalopram exhibited anti-depressant activity. In contrast, ibuprofen showed lesser activities against SNI-induced depression and pain. Further mechanistic studies revealed the uniqueness of puerarin as follows: (1) puerarin did not recover SNI-induced depletion of reduced glutathione and loss of superoxide dismutase (SOD), whereas citalopram and ibuprofen showed somewhat antioxidant activities; (2) puerarin markedly promoted the activation of CREB pathway although puerarin and citalopram activated ERK pathway to the same extent; (3) puerarin rapidly and persistently induced brain-derived neurotrophic factor (BDNF) expression whereas citalopram only induced BDNF expression after a prolonged stimulation. Collectively, these results suggest that puerarin may ameliorate the SNI-induced depression and pain via activating ERK, CREB, and BDNF pathways. Puerarin may serve as new lead compound for the development of novel therapeutics for depression and pain comorbidity.

No abstract

The resident microglial and infiltrating cells from peripheral circulation are involved in the pathological processes of ischemia stroke and may be regulated by mesenchymal stem/stromal cell (MSC) transplantation. The present study is aimed at differentiating the neurotrophic and inflammatory roles played by microglial vs. infiltrating circulation-derived cells in the acute phase in rat ischemic brains and explore the influences of intravenously infused allogeneic MSCs. The ischemic brain injury was induced by distal middle cerebral artery occlusion (dMCAO) in SD rats, with or without MSC infusion in the same day following dMCAO. Circulation-derived infiltrating cells in the brain were identified by Ly6C, a majority of which were monocytes/macrophages. Without MSC transplantation, among the infiltrated Ly6C+ cells, some were positive for BDNF, IL-1β, or TNF-α. Following MSC infusion, the overall number of Ly6C+ infiltrated cells was reduced by 50%. In contrast, the proportions of infiltrated Ly6C+ cells coexpressing BDNF, IL-1β, or TNF-α were significantly enhanced. Interestingly, Ly6C+ cells in the infarct area could produce either neurotrophic factor BDNF or inflammatory cytokines (IL-1β or TNF-α), but not both. This suggests that the Ly6C+ cells may constitute heterogeneous populations which react differentially to the microenvironments in the infarct area. The changes in cellular composition in the infarct area may have contributed to the beneficial effect of MSC transplantation.