TAT-PEP Alleviated Cognitive Impairment by Alleviating Neuronal Mitochondria Damage and Apoptosis After Cerebral Ischemic Reperfusion Injury.

Paired immunoglobulin-like receptor B (PirB) was identified as a myelin-associated inhibitory protein (MAIP) receptor that plays a critical role in axonal regeneration, synaptic plasticity and neuronal survival after stroke. In our previous study, a transactivator of transcription-PirB extracellular peptide (TAT-PEP) was generated that can block the interactions between MAIs and PirB. We found that TAT-PEP treatment improved axonal regeneration, CST projection and long-term neurobehavioural recovery after stroke through its effects on PirB-mediated downstream signalling. However, the effect of TAT-PEP on the recovery of cognitive function and the survival of neurons also needs to be investigated. In this study, we investigated whether pirb RNAi could alleviate neuronal injury by inhibiting the expression of PirB following exposure to oxygen-glucose deprivation (OGD) in vitro. In addition, TAT-PEP treatment attenuated the volume of the brain infarct and promoted the recovery of neurobehavioural function and cognitive function. This study also found that TAT-PEP exerts neuroprotection by reducing neuronal degeneration and apoptosis after ischemia-reperfusion injury. In addition, TAT-PEP improved neuron survival and reduced lactate dehydrogenase (LDH) release in vitro. Results also showed that TAT-PEP reduced malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) activity and reduced reactive oxygen species (ROS) accumulation in OGD-injured neurons. The possible mechanism was that TAT-PEP could contribute to the damage of neuronal mitochondria and affect the expression of cleaved caspase 3, Bax and Bcl-2. Our results suggest that PirB overexpression in neurons after ischaemic-reperfusion injury induces neuronal mitochondrial damage, oxidative stress and apoptosis. This study also suggests that TAT-PEP may be a potent neuroprotectant with therapeutic potential for stroke by reducing neuronal oxidative stress, mitochondrial damage, degeneration and apoptosis in ischemic stroke.

Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-κB/COX1 inflammatory signaling in ischemic cortex.

Post-stroke anxiety (PSA) is a kind of affective disorder occurring after a stroke, with anxiety as the primary clinical manifestation. PSA's mechanism is unclear, and there are few prevention and treatment measures. Our previous study found that HDAC3 could activate NF-κB signaling through mediated p65 deacetylation, which further influenced microglia activation. That implies HDAC3 may be the key mediator in ischemic stroke mice and modulates anxiety susceptibility to stress. This study established a PSA model in male C57BL/6 mice through photothrombotic stroke combined with chronic restrain stress. We focused on exploring whether esketamine administration can alleviate anxiety-like behavior and neuroinflammation, which may be associated with inhibiting HDAC3 expression and NF-κB pathway activation. The results showed that esketamine administration alleviated anxiety-like behavior in PSA mice. And the results showed that esketamine alleviated cortical microglial activation, altered microglial number, and kept morphology features. Furthermore, the results showed that the expression of HDAC3, phosphor-p65/p65, and COX1 significantly decreased in esketamine-treated PSA mice. Besides, we also found that esketamine reduced PGE2 expression, one of the primary regulators of negative emotions. Interestingly, our results indicate that esketamine reduced the perineuronal net (PNN) number in the pathological process of PSA. In conclusion, this study suggests esketamine could alleviate microglial activation, reduces inflammatory cytokine, and inhibits the expression of HDAC3 and NF-κB in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential therapeutic target for applying esketamine to PSA.

Omarigliptin Mitigates Lipopolysaccharide-Induced Neuroinflammation and Dysfunction of the Integrity of the Blood-Brain Barrier.

The blood-brain barrier (BBB) is an important barrier that separates brain tissue from peripheral blood. The permeability of the BBB can be destroyed by external harmful factors, such as lipopolysaccharide (LPS), which contributes to neuroinflammation and central nervous system diseases. The present study aims to investigate the protective effects of Omarigliptin against LPS-induced neuroinflammation and the underlying mechanism using a series of both in vivo and in vitro experiments. A neuroinflammation model was established by intraperitoneal injection of LPS into mice. We found that administration of Omarigliptin reduced LPS-induced inflammatory responses by inhibiting the expressions of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Importantly, we found that Omarigliptin protected the integrity of the BBB against LPS by increasing the expression of the tight junction proteins claudin-1 and claudin-5. Our results also demonstrate that Omarigliptin reduced LPS-induced increase in expressions of matrix matalloproteinases-2 (MMP-2) and matrix matalloproteinases-9 (MMP-9) at both the mRNA and protein levels. Notably, Omarigliptin showed a powerful beneficial effect against LPS-induced cell damage in bEnd.3 brain endothelial cells by reducing the release of high mobility group box chromosomal protein 1 (HMGB-1). Consistently, Omarigliptin ameliorated LPS-induced exacerbation of endothelial permeability by increasing the expressions of claudin-1 and claudin-5 and reducing the expression of MMP-2 and MMP-9. Mechanistically, Omarigliptin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor κB (TLR4/Myd88/NF-κB) signaling pathway. On the basis of these findings, we concluded that Omarigliptin might mitigate LPS-induced neuroinflammation and dysfunction of the integrity of the blood-brain barrier.