Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke.

Abstract Poor prognosis is often expected after the treatment of intracerebral haemorrhage (ICH) when the approach lacks effective neuroprotective interventions. Minocycline (Mino) is a promising clinical neuroprotective candidate for acute ICH therapy that mainly inhibits activation of microglia/macrophages. However, to address iron neurotoxicity, ferroptosis, and oxidative stress‐induced multiple neuroinjury mechanisms, the neuroprotective effect of minocycline still urgently needs to be enhanced. To address this issue, procyanidins (PACs), typical natural polyphenols, is used to improve the neuroprotective effect of Mino by constructing PACs‐Mino nanoparticles (NPs) using 3‐aminophenylboronic acid as the crosslinker. The yielding NPs possessed improved antioxidant and iron‐removing capacities in vitro. More importantly, PACs‐Mino NPs exerted excellent therapeutic effects on ICH, showing improved neuroprotective activity and resulting in neurobehavioral recovery, in an in vitro cellular model and an in vivo ICH rat model. This study can provide a general strategy that uses natural polyphenols to boost the performance of drugs for ICH treatment, and the results may be further extended to other injuries of the central nervous system, such as brain injury and spinal cord injury. 

Procyanidins Boost the Neuroprotective Effect of Minocycline for Intracerebral Haemorrhage

Mechanisms of cerebrospinal fluid and brain interstitial fluid production

Both functional brain imaging studies and autopsy reports have indicated the presence of synaptic loss in the brains of depressed patients. The activated microglia may dysfunctionally engulf neuronal synapses, leading to synaptic loss and behavioral impairments in depression. However, the mechanisms of microglial-synaptic interaction under depressive conditions remain unclear. We utilized lipopolysaccharide (LPS) to induce a mouse model of depression, examining the effects of LPS on behaviors, synapses, microglia, microglial phagocytosis of synapses, and the C1q/C3-CR3 complement signaling pathway. Additionally, a C1q neutralizing antibody was employed to inhibit the C1q/C3-CR3 signaling pathway and assess its impact on microglial phagocytosis of synapses and behaviors in the mice. LPS administration resulted in depressive and anxiety-like behaviors, synaptic loss, and abnormal microglial phagocytosis of synapses in the hippocampal dentate gyrus (DG) of mice. We found that the C1q/C3-CR3 signaling pathway plays a crucial role in this abnormal microglial activity. Treatment with the C1q neutralizing antibody moderated the C1q/C3-CR3 pathway, leading to a decrease in abnormal microglial phagocytosis, reduced synaptic loss, and improved behavioral impairments in the mice. The study suggests that the C1q/C3-CR3 complement signaling pathway, which mediates abnormal microglial phagocytosis of synapses, presents a novel potential therapeutic target for depression treatment. 

Complement C1q/C3-CR3 signaling pathway mediates abnormal microglial phagocytosis of synapses in a mouse model of depression

Abstract Background Hydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction. Methods Magnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay. Results SHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na + /K + /2Cl − cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats. Conclusion Hydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics. 

https://fluidsbarrierscns.biomedcentral.com/counter/pdf/10.1186/s12987-023-00448-x

Spontaneously hypertensive rats can become hydrocephalic despite undisturbed secretion and drainage of cerebrospinal fluid

Aim The complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined. Methods There were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined. Results There were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1. Conclusions The complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.

/pdf/role-of-complement-c1q-c3-cr3-signaling-in-brain-injury-b8jbc9ca.pdf

Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment

Background The relationship between neutrophil to lymphocyte ratio (NLR) and poor outcome of aneurysmal subarachnoid hemorrhage (aSAH) is controversial. We aim to evaluate the relationship between NLR on admission and the poor outcome after aSAH. Method Part I: Retrospective analysis of aSAH patients in our center. Baseline characteristics of patients were collected and compared. Multivariate analysis was used to evaluate parameters independently related to poor outcome. Receiver operating characteristic (ROC) curve analysis was used to determine the best cut-off value of NLR. Part II: Systematic review and meta-analysis of relevant literature. Related literature was selected through the database. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the correlation between NLR and outcome measures. Results Part I: A total of 240 patients with aSAH were enrolled, and 52 patients had a poor outcome. Patients with poor outcome at 3 months had a higher admission NLR, Hunt & Hess score, Barrow Neurological Institute (BNI) scale score, Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and proportion of hypertension history. After adjustment, NLR at admission remained an independent predictor of poor outcome in aSAH patients (OR 0.76, 95% CI 0.69-0.83; P < 0.001). The best cut-off value of NLR in ROC analysis is 12.03 (area under the curve 0.805, 95% CI 0.735 - 0.875; P < 0.001). Part II: A total of 16 literature were included. Pooled results showed that elevated NLR was significantly associated with poor outcome (OR 1.31, 95% CI 1.14-1.49; P < 0.0001) and delayed cerebral ischemia (DCI) occurrence (OR 1.32, 95% CI 1.11-1.56; P = 0.002). The results are more reliable in large sample sizes, low NLR cut-off value, multicenter, or prospective studies. Conclusion Elevated NLR is an independent predictor of poor outcome and DCI occurrence in aSAH.

/pdf/neutrophil-to-lymphocyte-ratio-predicting-poor-outcome-after-3tml583r.pdf

Neutrophil to lymphocyte ratio predicting poor outcome after aneurysmal subarachnoid hemorrhage: A retrospective study and updated meta-analysis

Hydrocephalus has been observed in rats with spontaneous hypertension (SHRs). It has been demonstrated that activation of the oxidative stress related protein retinoic acid receptor alpha (RARα) has neuroprotective impacts. Our investigation aims to determine the potential role and mechanism of RARα in hydrocephalus. The RARα-specific agonist (Am80) and RARα inhibitor (AGN196996) were used to investigate the role of RARα in cerebrospinal fluid (CSF) secretion in the choroid plexus of SHRs. Evaluations of CSF secretion, ventricular volume, Western blotting, and immunofluorescent staining were performed. Hydrocephalus and CSF hypersecretion were identified in SHRs but not in Wistar–Kyoto rats, occurring at the age of 7 weeks. The RARα/MAFB/MSR1 pathway was also activated in SHRs. Therapy with Am80 beginning in week 5 decreased CSF hypersecretion, hydrocephalus development, and pathological changes in choroid plexus alterations by week 7. AGN196996 abolished the effect of Am80. In conclusion, activation of the RARα attenuated CSF hypersecretion to inhibit hydrocephalus development via regulating the MAFB/MSR1 pathway. RARα may act as a possible therapeutic target for hydrocephalus.

/pdf/activation-of-the-rara-attenuated-csf-hypersecretion-to-k5cacxko.pdf

Activation of the RARα Attenuated CSF Hypersecretion to Inhibit Hydrocephalus Development via Regulating the MAFB/MSR1 Pathway

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Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment

Neutrophil to lymphocyte ratio predicting poor outcome after aneurysmal subarachnoid hemorrhage: A retrospective study and updated meta-analysis

Activation of the RARα Attenuated CSF Hypersecretion to Inhibit Hydrocephalus Development via Regulating the MAFB/MSR1 Pathway