Propofol Mediated Protection of the Brain From Ischemia/Reperfusion Injury Through the Regulation of Microglial Connexin 43

Abstract

Cerebral ischemia/reperfusion (I/R) injury is a serious condition that leads to increased apoptosis of microglial and neurons in the brain. In this study, we identified that Cx43 expression level is significantly increased in the microglial cells during I/R injury. Using an in vitro model (hypoxia/reoxygenation-H/R injury), we observed that H/R injury leads to an increase in activation of microglial cells and increase in levels of pro-inflammatory markers such as IL-1β, IL-6, and TNF-α. Additionally, we could also observe significant increase in phosphorylation of Cx43 and Cav3.2 levels. To assess the role of H/R injured microglial cells on neuronal population, we cultured the neurons with conditioned media (MCS) from H/R injured microglial cells. Interestingly, we observed that microglial H/R injury significantly decreased Map2 expression and affected neuronal morphology. Further, we aimed to assess the effects of propofol on cerebral H/R injury, and observed that 40 μM propofol significantly decreased Cx43, Cx43 phosphorylation, and CaV3.2 levels. Additionally, propofol decreased apoptosis and increased Map2 expression levels in H/R injured neurons. Using silencing experiments, we confirmed that siCx43 could significantly improve the propofol’s rescue after H/R injury in both microglia and neurons. We further developed an in vivo MCAO (middle cerebral artery occlusion) rat model to understand the effect of propofol in I/R injury. Interestingly, propofol treatment and downregulation of Cx43 significantly decreased the infract volume and apoptosis in these MCAO rats. Thus, this study clearly establishes that propofol protects the brain against I/R injury through the downregulation of Cx43 in microglial cells.

Establishment of the reproducible branch retinal artery occlusion mouse model and intravital longitudinal imaging of the retinal CX3CR1-GFP+ cells after spontaneous arterial recanalization

“…There are several reports that microglia is involved in the reaction of the IR injury in MI and stroke (24,25,59). However, the role of the microglia is still not fully understood and remains obscure with controversies.…”

“…Thus, much research about this ischemia-reperfusion (IR) injury have been conducted in multiple fields, including cardiology and neurology (22,23). There are also several reports that microglia is activated by IR injury in cerebral infarction (24)(25)(26). However, the dynamics of retinal microglia mediating IR injury has not been well investigated yet.…”

Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia

“…To further explore the anti-apoptotic effect of NRP-1, we detected the TUNEL-positive cells and protein levels of Bax, Bcl-2, Cleaved caspase-3, and Caspase-3 in tMCAO rats. A recent study evidences that TUNEL-positive cells are apoptotic in nature [ 49 ]. The Bcl-2 family and the cysteine proteases known as caspases play an important role in apoptosis, in which both Bax and Bcl-2 belong to the Bcl-2 family, with the former as an anti-apoptotic gene and the latter as an pro-apoptotic gene[ 50 ].…”

Inflammatory responses involved in post-cardiac arrest brain injury: mechanisms, regulation, and therapeutic potential

“…Evidence from in vitro [115] and in vivo [116] studies indicate that propofol can modulate microglial activation and has potential anti-inflammatory functions. Propofol induces the anti-inflammatory treatment by suppressing microglial activation after CA and TNF-α and IL-1β release, likely via the purinergic ligand-gated ion channel 7 receptor (P2X7R)/phosphor-p38 (p-p38) pathway [117].…”