Background and purpose: To investigate the association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) with post-thrombolysis early neurological outcomes including early neurological improvement (ENI) and early neurological deterioration (END) in patients with acute ischemic stroke (AIS).Methods: AIS patients undergoing intravenous thrombolysis were enrolled from April 2016 to September 2019. Blood cell counts were sampled before thrombolysis. Post-thrombolysis END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase of ≥ 4 within 24 h after thrombolysis. Post-thrombolysis ENI was defined as NIHSS score decrease of ≥ 4 or complete recovery within 24 h. Multinomial logistic regression analysis was performed to explore the relationship of NLR, PLR, and LMR to post-thrombolysis END and ENI. We also used receiver operating characteristic curve analysis to assess the discriminative ability of three ratios in predicting END and ENI.Results: Among 1060 recruited patients, a total of 193 (18.2%) were diagnosed with END and 398 (37.5%) were diagnosed with ENI. Multinomial logistic model indicated that NLR (odds ratio [OR], 1.385; 95% confidence interval [CI] 1.238–1.551,P= 0.001), PLR (OR, 1.013; 95% CI 1.009–1.016,P= 0.001), and LMR (OR, 0.680; 95% CI 0.560–0.825,P= 0.001) were independent factors for post-thrombolysis END. Moreover, NLR (OR, 0.713; 95% CI 0.643–0.791,P= 0.001) served as an independent factor for post-thrombolysis ENI. Area under curve (AUC) of NLR, PLR, and LMR to discriminate END were 0.763, 0.703, and 0.551, respectively. AUC of NLR, PLR, and LMR to discriminate ENI were 0.695, 0.530, and 0.547, respectively.Conclusions: NLR, PLR, and LMR were associated with post-thrombolysis END. NLR and PLR may predict post-thrombolysis END. NLR was related to post-thrombolysis ENI.

Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed ‘pyroptosis’, which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process. We first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats. Western blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis. Our data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.

BACKGROUND AND PURPOSE Angiotensin‐(1‐7) [Ang‐(1‐7)] has anti‐inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti‐inflammatory effect contributes to the neuroprotection induced by Ang‐(1‐7) in a rat model of permanent middle cerebral artery occlusion (pMCAO).EXPERIMENTAL APPROACH We infused Ang‐(1‐7), Mas receptor antagonist A‐779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague‐Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty‐four hours after pMCAO, the neuroprotective effect of Ang‐(1‐7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF‐κB was assessed by Western blot and immunohistochemistry analysis. The level of COX‐2 was tested by Western blot analysis and concentrations of pro‐inflammatory cytokines were measured by elisa.KEY RESULTS Infusion of Ang‐(1‐7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF‐κB activity, which was accompanied by a reduction of pro‐inflammatory cytokines and COX‐2 in the peri‐infarct regions. These effects of Ang‐(1‐7) were reversed by A‐779 but not by PD123319. Additionally, infusion of A‐779 alone increased oxidative stress levels and enhanced NF‐κB activity, which was accompanied by an up‐regulation of pro‐inflammatory cytokines and COX‐2.CONCLUSION AND IMPLICATIONS Our findings indicate that suppressing NF‐κB dependent pathway via Mas receptor may represent one mechanism that contributes to the anti‐inflammatory effects of Ang‐(1‐7) in rats with pMCAO.

NLRP3 inflammasome is proposed to regulate inflammation in several neurological diseases, but its role in epilepsy remains largely unknown. This study aimed to investigate the role of the NLRP3 inflammasome in neuroinflammation, spontaneous recurrent seizures (SRS) and hippocampal neuronal loss in rat brain following amygdala kindling-induced status epilepticus (SE). We detected the protein levels of IL-1β and NLRP3 inflammasome components by Western blot in the hippocampus of shams and SE rats at different time points following SE. To further examine whether the activation of the NLRP3 inflammasome contributes to SE-associated neuronal damage, we employed a nonviral strategy to knock down NLRP3 and caspase-1 expression in brain before undergoing SE. Proinflammatory cytokine levels and hippocampal neuronal loss were evaluated at 12 hours and at 6 weeks following SE respectively in these NLRP3 and caspase-1 deficient rats. Meanwhile, SRS occurrence was evaluated through a 4-week video recording started 2 weeks after SE in these NLRP3 and caspase-1 deficient rats. IL-1β levels and NLRP3 inflammasome components levels dramatically increased at 3 hours after SE, and reached a maximum at 12 hours after SE compared with the control group. Knock down of NLRP3 or caspase-1 decreased the levels of IL-1β and IL-18 at 12 hours after SE, which was accompanied by a significant suppression in the development and severity of SRS during the chronic epileptic phase. Meanwhile, knock down of NLRP3 or caspase-1 led to a remarkable reduction of hippocampal neuronal loss in the CA1 and CA3 area of the hippocampus at 6 weeks after SE. Our study provides the first evidence that the NLRP3 inflammasome was significantly up-regulated following SE. More importantly, we show that inhibition of the NLRP3 inflammasome provides neuroprotection in rats following SE. These findings suggest that NLRP3 may represent a potential target for the treatment of epileptogenesis

Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer’s disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. In the presence or absence of neurons, oligomeric amyloid beta (oAβ)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAβ-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. In the present study, we showed that PM2.5 exposure aggravated oAβ-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1β production. Further, PM2.5-induced IL-1β production in oAβ-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAβ-stimulated microglia. ROS was required for PM2.5-induced IL-1β production and NLRP3 inflammasome activation in oAβ-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.