Reduce Brain Damage Research Articles

Abstract TMP98: Pre-Stroke Use of Blood-Brain Barrier Crossing Angiotensin Receptor Blockers in Elderly Patients Mitigates Neurological Severity at the Onset of Acute Stroke

Introduction: Functional outcomes after acute stroke (AS) are related to the initial neurological severity. Therefore, using neuroprotective agents to prevent or reduce brain damage shows promise as a preventive approach. Blood-brain barrier crossing (BBBc) angiotensin receptor blockers (ARBs) have been reported to reduce the risk of cognitive disorders. Therefore, BBBc ARBs may exert neuroprotective effects on brain damage caused by AS. However, the association between pre-stroke BBBc ARB use and neurological severity at the onset of AS has not been well studied. Hypothesis: Pre-stroke BBBc ARBs in elderly patients is linked to mild neurological severity (MNS) at the time of AS onset. Methods: We retrospectively included patients admitted within 24 hours of AS onset between January 2013 and March 2019 with available pre-stroke medication information. We defined MNS as a score of ≤5 points on the National Institutes of Health Stroke Scale. We conducted logistic regression analysis using variables for pre-stroke BBBc ARBs initiation, calculated propensity scores for pre-stroke BBBc ARBs use, and implemented one-to-one propensity score matching (PSM). The McNemar test assessed whether pre-stroke BBBc ARBs administration significantly affected MNS. Results: Out of 4294 patients with AS, 3472 met the inclusion criteria. Following one-to-one PSM, we identified 508 patients each in the BBBc ARBs usage and non-usage groups. The median ages of BBBc ARBs users and non-users were 80 and 81 years, respectively. Among the 508 BBBc ARBs users and the 508 non-users, 325 and 278 patients exhibited MNS, respectively (p=0.0027). Furthermore, the McNemar test revealed an asymmetrical binary matched pairs contingency table of MNS (p=0.0021), indicating a significant association between pre-stroke BBBc ARB use and MNS at the time of AS onset. Conclusions: The pre-stroke utilization of BBBc ARBs among elderly patients is associated with MNS at the onset of AS, implying potential neuroprotective effects against AS-induced brain damage. Further prospective studies are warranted to validate our findings and establish the practical application of BBBc ARBs for neuroprotection before AS.

The neuroprotective effect of near infrared light therapy in aged mice with postoperative neurocognitive disorder by upregulating IRF7

BackgroundPostoperative neurocognitive disorder (PND) is a common central nervous system complication after undergoing surgery and anesthesia especially in elderly patients, while the therapeutic options are very limited. This study was carried out to investigate the beneficial effects of transcranial near infrared light (NIRL) which was employed to the treatment of PND and propose the involved mechanisms. MethodsThe PND mice were established through left carotid artery exposure under isoflurane anesthesia and received transcranial NIRL treatment. Behavioral testing was performed to evaluate the cognitive function of PND mice after transcranial NIRL therapy. Changes in the transcriptomic profiles of prefrontal cortex (PFC) and hippocampus (HP) were identified by next generation sequencing (NGS), and the molecular mechanisms involved were examined by both in vivo mouse model and in vitro cell culture studies. ResultsWe found that transcranial NIRL therapy effectively ameliorated learning and memory deficit induced by anesthesia and surgery in aged mice. Specifically, we identified down-regulation of interferon regulatory factor 7 (IRF7) in the brains of PND mice that was mechanistically associated with increased pro-inflammatory M1 phenotype of microglia and elevated neuroinflammatory. NIRL treatment produced protective effects through the upregulation of IRF7 expression and reversing microglial phenotypes from pro-inflammatory to neuroprotective, resulting in reduced brain damage and improved cognitive function in PND mice. ConclusionOur results indicate that transcranial NIRL is an effective and safe therapy for PND via alleviating neuroinflammation, and IRF7 plays a key transcription factor in regulating the M1-to-M2 switch of microglia.

MiR-96-5p alleviates cerebral ischemia-reperfusion injury in mice by inhibiting pyroptosis via downregulating caspase 1

Ischemic stroke is one of the leading causes of global mortality and disability. Nevertheless, successful treatment remains limited. In this study, we investigated the efficacy and the mechanism of miR-96-5p in protecting acute ischemic brain injury in adult mice. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice. MiR-96-5p or the negative control was administered via intracerebroventricular injection. The expression of pyroptosis-related genes and activation of various resident cells in the brain was assessed by RT-qPCR, western blot, immunohistochemistry, and immunofluorescence. Modified neurological severity score, rotarod test, cylinder test, brain water content, and cerebral infarction volume were used to evaluate the behavioral deficits and the severity of brain injury after MCAO. Flow cytometry, TUNEL staining, and Nissl staining were employed to assess the neuron damage. MiR-96-5p decreased markedly in the ischemic stroke model in vivo and in vitro. MiR-96-5p mimics suppressed the expression of caspase 1 and alleviated the apoptosis rate in OGD/R treatment N2a cells, however, the miR-96-5p inhibitor caused the opposite results. Intracerebroventricular delivery of miR-96-5p agomir significantly mitigated behavioral deficits, brain water content, and cerebral infarction volume after MCAO. In addition, treatment with miR-96-5p agomir downregulated the expression of caspase 1/cleaved caspase 1 and Gsdmd/Gsdmd-N, while alleviating the neuron damage. In summary, overexpression of miR-96-5p suppresses pyroptosis and reduces brain damage in the acute phase of ischemic stroke, providing new insight into the treatment of acute ischemic stroke.

PI3K/AKT and STAT3 pathways mediate the neuroprotective effect of dasatinib from acute cerebral injury in endotoxemic mice.

Sepsis induces brain dysfunction and there is still a requirement for an unemployed viable restorative approach. This study aimed to investigate the role of dasatinib in the modulation of proinflammatory mediators, attenuating neuroinflammatory response, and it's signaling pathway during endotoxemia. Twenty-four adult male Swiss-albino mice were randomized into four groups: sham (undergo laparotomy without cecal ligation and puncture, sepsis (laparotomy with cecal ligation and puncture), vehicle-dimethyl sulfoxide, dasatinib (20 mg/kg/day) intraperitoneally. Brain tissue used for assessment of interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), IL-10, Toll-like receptor 4 (TLR4), protein kinase B (AKT), phosphoinositide 3-kinases (PI3K), signal transducer and activator of transcription 3 (STAT3), and histopathological examination. Brain tissue levels of TNF-α, IL-6, and IL1 β were higher in the sepsis group than in the sham and vehicle groups. The dasatinib group had considerably lower tissue levels of these markers and significantly higher tissue values of IL-10 than the sepsis and vehicle groups. The sham group had much lower tissue values of TLR4, AKT, STAT3, and PI3k than in sepsis and vehicle groups. Furthermore, tissue levels of these markers in the dasatinib group were considerably lower than those in the sepsis and vehicle groups. Histopathology demonstrated that dasatinib might considerably reduce brain damage and the intensity of neuroinflammation when compared to sepsis and vehicle groups that showed extensive brain inflammation and damage. Dasatinib attenuated endotoxemia-induced acute brain damage in mice via modulating effects on TLR4, PI3K, AKT, and STAT3 downstream signaling pathways.

Role of factor XIII in ischemic stroke: a key molecule promoting thrombus stabilization and resistance to lysis

BackgroundActive coagulation factor XIII (FXIII) catalyzing crosslinking of fibrin and other hemostatic factors plays a key role in clot stability and lysis. ObjectivesTo evaluate the effect of FXIII inhibition in a mouse model of ischemic stroke (IS) and the role of activated FXIII (FXIIIa) in clot formation and lysis in patients with IS. MethodsA ferric chloride IS murine model was performed before and after administration of a FXIIIa inhibitor (FXIIIinh). Thromboelastometry in human and mice blood was used to evaluate thrombus stiffness and lysis with FXIIIinh. FXIIIa-dependent fibrin crosslinking and lysis with fibrinolytic drugs (tissue plasminogen activator and tenecteplase) were studied on fibrin plates and on thrombi and clotted plasma of patients with IS. Finally, circulating and thrombus FXIIIa were measured in 85 patients with IS. ResultsFXIIIinh administration before stroke induction reduced infarct size, α2-antiplasmin (α2AP) crosslinking, and local microthrombosis, improving motor coordination and fibrinolysis without intracranial bleeds (24 hours). Interestingly, FXIII blockade after stroke also reduced brain damage and neurologic deficit. Thromboelastometry in human/mice blood with FXIIIinh showed delayed clot formation, reduced clot firmness, and shortened tissue plasminogen activator lysis time. FXIIIa fibrin crosslinking increased fibrin density and lysis resistance, which increased further after α2AP addition. FXIIIinh enhanced ex vivo lysis in stroke thrombi and fibrin plates. In patients with IS, thrombus FXIII and α2AP were associated with inflammatory and hemostatic components, and plasma FXIIIa correlated with thrombus α2AP and fibrin. ConclusionOur results suggest a key role of FXIIIa in thrombus stabilization, α2AP crosslinking, and lysis resistance, with a protective effect of FXIIIinh in an IS experimental model.

Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria.

The microRNA-21 (miR-21) levels in the brain are crucial in determining post-stroke brain damage and recovery. The miR-21 exerts neuroprotection by targeting mRNAs that translate proteins that mediate brain damage. We currently determined the efficacy and efficiency of intravenously administered miR-21 mimic after focal cerebral ischemia in mice. Adult male mice were intravenously administered with either control mimic or miR-21 mimic at 5min/2 h after reperfusion following 1h transient middle cerebral artery occlusion to determine the therapeutic window of miR-21 mimic. Adult female, type-2 diabetic male, aged male, and aged female mice were administered with control/miR-21 mimic at 5 min after reperfusion following 35min/1h transient middle cerebral artery occlusion. Early administration of miR-21 mimic significantly reduced brain damage and promoted long-term recovery after stroke. Further, miR-21 mimic is more effective in males than in females subjected to stroke. However, delayed treatment with miR-21 mimic is not efficacious, and type-2 diabetic subjects show no improvement with miR-21 mimic treatment.

Celecoxib treatment alleviates cerebral injury in a rat model of post-traumatic epilepsy

Background An important factor contributing to the development and occurrence of post-traumatic epilepsy (PTE) is neuroinflammation and oxidative stress. The effects of celecoxib include inhibiting inflammatory reactions and antioxidant stress and reducing seizures, making it a potential epilepsy treatment solution. Objective To observe the effect of celecoxib on early epilepsy in post-traumatic epilepsy rats. Methods: Twenty-four adult healthy male Sprague-Dawley rats were randomly assigned to three groups: sham-operated, PTE, and celecoxib. A rat model of PTE was established by injecting ferrous chloride into the right frontal cortex. Afterward, the behavior of rats was observed and recorded. 3.0T superconducting magnetic resonance imaging (MRI) was used to describe the changes in ADC values of the brain. HE and Nissl staining were also used to detect the damage to frontal lobe neurons. Furthermore, the expression of COX-2 protein in the right frontal lobe was detected by Western blot. Moreover, the contents of IL-1 and TNF-α in the right frontal lobe were detected by enzyme-linked immunosorbent assay. Results Compared with the PTE group, the degree of seizures in rats treated with celecoxib declined dramatically (P < 0.05). Celecoxib-treated rats had significant decreases in tissue structural damage and cell death in the brain. The results of the MRI showed that celecoxib reduced the peripheral edema zone and ADC value of the cortex around the damaged area of the right frontal lobe in the celecoxib-treatment group, which was significantly decreased compared with the PTE group (P < 0.05). Furthermore, celecoxib decreased the expression of COX-2, IL-1β, and TNF-α in brain tissue (P < 0.05). Conclusions In PTE rats, celecoxib significantly reduced brain damage and effectively reduced seizures. As a result of celecoxib’s ability to inhibit inflammation, it can reduce the edema caused by injury in rat brain tissue.

Non-alcoholic fatty liver disease is associated with brain function disruption in type 2 diabetes patients without cognitive impairment.

To investigate the neural static and dynamic intrinsic activity of intra-/inter-network topology among patients with type 2 diabetes (T2D) with non-alcoholic fatty liver disease (NAFLD) and those without NAFLD (T2NAFLD group and T2noNAFLD group, respectively) and to assess the relationship with metabolism. Fifty-six patients with T2NAFLD, 78 with T2noNAFLD, and 55 healthy controls (HCs) were recruited to the study. Participants had normal cognition and underwent functional magnetic resonance imaging scans, clinical measurements, and global cognition evaluation. Independent component analysis was used to identify frequency spectrum parameters, static functional network connectivity, and temporal properties of dynamic functional network connectivity (P < 0.05, false discovery rate-corrected). Statistical analysis involved one-way analysis of covariance with post hoc, partial correlation and canonical correlation analyses. Our findings showed that: (i) T2NAFLD patients had more disordered glucose and lipid metabolism, had more severe insulin resistance, and were more obese than T2noNAFLD patients; (ii) T2D patients exhibited disrupted brain function, as evidenced by alterations in intra-/inter-network topology, even without clinically measurable cognitive impairment; (iii) T2NAFLD patients had more significant reductions in the frequency spectrum parameters of cognitive executive and visual networks than those with T2noNAFLD; and (iv) altered brain function in T2D patients was correlated with postprandial glucose, high-density lipoprotein cholesterol, and waist-hip ratio. This study may provide novel insights into neuroimaging correlates for underlying pathophysiological processes inducing brain damage in T2NAFLD. Thus, controlling blood glucose levels, lipid levels and abdominal obesity may reduce brain damage risk in such patients.

T817MA Regulates Mitochondrial Dynamics via Sirt1 and Arc Following Subarachnoid Hemorrhage.

Spontaneous subarachnoid hemorrhage (SAH) is an acute neurologic emergency with poor outcomes, and mitochondrial dysfunction is known as one of the key pathological mechanisms underlying the SAH-induced early brain injury (EBI). 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate (T817MA) is a newly synthesized neurotrophic compound that has been demonstrated to exert protective effects against brain injury. Here, we investigated the effect of T817MA in neuronal injury following experimental SAH both in vitro and in vivo. Primary cultured cortical neurons were treated with oxyhemoglobin (OxyHb) to mimic SAH in vitro, and T817MA at concentrations higher than 0.1μM reduced OxyHb-induced neuronal injury. T817MA treatment significantly inhibited lipid peroxidation, reduced neuronal apoptosis and attenuated mitochondrial fragmentation. The results of western blot showed that T817MA markedly reduced the expression of mitochondrial fission proteins, fission protein 1 (Fis-1) and dynamin-related GTPase-1 (Drp-1), but prolonged the expression of the postsynaptic protein activity-regulated cytoskeleton-associated protein (Arc). In addition, T817MA significantly increased the expression of sirtuin 1 (Sirt1), which was accompanied by preserved enzymatic of isocitrate dehydrogenase (IDH2) and superoxide dismutase (SOD). Knockdown of Sirt1 and Arc via small interfere RNA (siRNA) transfection partially prevented the T817MA-induced protection in cortical neurons. Furthermore, treatment with T817MA in vivo significantly reduced brain damage and preserved neurological function in rats. The decreased expression of Fis-1 and Drp-1, as well as the increased expression of Arc and Sirt1 were also observed in vivo. Taken together, these data indicate that the neuroprotective agent T817MA protects against SAH-induced brain injury via Sirt1- and Arc-mediated regulation of mitochondrial dynamics.

Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats.

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O2 for 60') (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5-33.5 °C) was performed (5 h duration) using Criticool®. The animals were divided according to diet, injury and thermal condition. At P8 (24 h after HI), the brain neurochemical profile was assessed using magnetic resonance spectroscopy (1H-MRS) and a hyperintense T2W signal was used to measure the brain lesions. The mRNA levels of the genes related to glutamatergic excitotoxicity, energy metabolism and inflammation were assessed in the right hippocampus. The cell markers and apoptosis expression were assessed using immunofluorescence in the right hippocampus. HI decreased the energy metabolites and increased lactate. The neuronal-astrocytic coupling impairments observed in the HI groups were reversed mainly by HT. LF had an important effect on astrocyte function, decreasing the levels of the genes related to glutamatergic excitotoxicity and restoring the mRNA levels of the genes related to metabolic support. When combined, LF and HT presented a synergistic effect and prevented lactate accumulation, decreased inflammation and reduced brain damage, pointing out the benefits of combining these therapies. Overall, we showed that through distinct mechanisms lactoferrin can enhance neuroprotection induced by HT following neonatal brain hypoxia-ischemia.

Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy.

High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins' interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an "informed" selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation.

Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.

PREDICTION OF STROKE USING EEG SIGNALS

A stroke is a disruption of blood supply to the brain that leads to disability. Rehabilitation can reduce brain damage and other complications and also recover disability due to stroke. One instrument that can be used in post-stroke patients monitoring is Electroencephalogram (EEG). EEG signals are recorded from several channel pairs. So apart from maintaining signal sequences, handling time connectivity between channels is also essential. Therefore, the signal sequence and time connectivity between channels need to be handled simultaneously on two dimensions. The vertical dimension was the multi-channel dimension, and the horizontal dimension was the signal sequences of each channel concerning time. The proposed system uses the 2D-Convolutional Neural Networks method to identify post-stroke based on EEG signals. First, a wavelet filter was used to obtain a frequency range of 1–13 Hz to represent post-stroke patients. The identification results are one of the three levels of stroke, i.e., No Stroke and Minor Stroke.

Hypothermic neuroprotection by targeted cold autologous blood transfusion in a non-human primate stroke model

Over decades, nearly all attempts to translate the benefits of therapeutic hypothermia in stroke models of lower-order species to stroke patients have failed. Potentially overlooked reasons may be biological gaps between different species and the mismatched initiation of therapeutic hypothermia in translational studies. Here, we introduce a novel strategy of selective therapeutic hypothermia in a non-human primate ischemia-reperfusion model, in which autologous blood was cooled ex vivo and the cool blood transfusion was administered at the middle cerebral artery just after the onset of reperfusion. Cold autologous blood cooled the targeted brain rapidly to below 34 °C while the rectal temperature remained around 36 °C with the assistance of a heat blanket during a 2-h hypothermic process. Therapeutic hypothermia or extracorporeal-circulation related complications were not observed. Cold autologous blood treatment reduced infarct sizes, preserved white matter integrity, and improved functional outcomes. Together, our results suggest that therapeutic hypothermia, induced by cold autologous blood transfusion, was achieved in a feasible, swift, and safe way in a non-human primate model of stroke. More importantly, this novel hypothermic approach conferred neuroprotection in a clinically relevant model of ischemic stroke due to reduced brain damage and improved neurofunction. This study reveals an underappreciated potential for this novel hypothermic modality for acute ischemic stroke in the era of effective reperfusion.

The Long-Term Neuroprotective Effect of the Endocannabinoid 2-AG and Modulation of the SGZ's Neurogenic Response after Neonatal Hypoxia-Ischemia.

Neonatal hypoxia-ischemia (HI) often causes hypoxic-ischemic encephalopathy (HIE), a neurological condition that can lead to overall disability in newborns. The only treatment available for affected neonates is therapeutic hypothermia; however, cooling is not always effective to prevent the deleterious effects of HI, so compounds such as cannabinoids are currently under research as new therapies. Modulating the endocannabinoid system (ECS) may reduce brain damage and/or stimulate cell proliferation at the neurogenic niches. Further, the long-term effects of cannabinoid treatment are not so clear. Here, we studied the middle- and long-term effects of 2-AG, the most abundant endocannabinoid in the perinatal period after HI in neonatal rats. At middle-term (postnatal day 14), 2-AG reduced brain injury and increased SGZ's cell proliferation and the number of neuroblasts. At post-natal day 90, the treatment with the endocannabinoid showed global and local protection, suggesting long-lasting neuroprotective effects of 2-AG after neonatal HI in rats.

AT 1 inhibition mediated neuroprotection after experimental traumatic brain injury is dependent on neutrophils in male mice

After traumatic brain injury (TBI) cerebral inflammation with invasion of neutrophils and lymphocytes is a crucial factor in the process of secondary brain damage. In TBI the intrinsic renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) reduces secondary brain damage and the invasion of neutrophil granulocytes into injured cerebral tissue. The current study explored the involvement of immune cells in neuroprotection mediated by AT1 inhibition following experimental TBI. Four different cohorts of male mice were examined, investigating the effects of neutropenia (anti-Ly6G antibody mediated neutrophil depletion; C57BL/6), lymphopenia (RAG1 deficiency, RAG1−/−), and their combination with candesartan-mediated AT1 inhibition. The present results showed that reduction of neutrophils and lymphocytes, as well as AT1 inhibition in wild type and RAG1−/− mice, reduced brain damage and neuroinflammation after TBI. However, in neutropenic mice, candesartan did not have an effect. Interestingly, AT1 inhibition was found to be neuroprotective in RAG1−/− mice but not in neutropenic mice. The findings suggest that AT1 inhibition may exert neuroprotection by reducing the inflammation caused by neutrophils, ultimately leading to a decrease in their invasion into cerebral tissue.

Numerous Types of Stem Cells Possess Potential to Treat Congenital Hydrocephalus

Twenty-five percent of premature neonate’s experience Intraventricular Hemorrhage (IVH) and 10% of these events are complicated further by the occurrence of hydrocephalus. The number of infants at high risk for IVH and therefore Post Hemorrhagic Hydrocephalus (PHH), is rising due to improved survival rate of premature infants. Fetal onset hydrocephalus is a heterogeneous brain disorder involving Cerebrospinal Fluid (CSF) dynamics and is a result of both genetic and environmental factors. Mesenchymal stem cells present themselves as a potent therapeutic modality for brain injury based on their multipotency, anti-inflammatory, antioxidant and angiogenic functions. Numerous animal model clinical provide evidence that Mesenchymal Stem Cells (MSCs) can target nearly all mechanisms involved in the pathogenesis of hydrocephalus. Unrestricted somatic stem cells possess anti-inflammatory and immunomodulatory properties as well as release growth factors and cytokines with known neuroprotective and axonal growth promoting functions. Neural stem cells are self-sustaining, pluripotent cells that have the capability to correct brain maldevelopment, reduce brain damage, promote regeneration and repair via neurotrophic and immunomodulatory mechanisms and direct cell replacement. For these reasons, stem cells possess the potential to be an effective therapy and should be further researched.

Chloroquine Protects Hypoxia/Ischemia-Induced Neonatal Brain Injury in Rats by Mitigating Blood-Brain Barrier Disruption.

Neonatal hypoxic-ischemic (H/I) brain damage (HIBD) is a devastating condition for which there are presently no effective therapeutic strategies against its severe neurological deficits in neonates and young children. Traditionally, H/I induces the compromise of the blood-brain barrier (BBB), which causes neuronal cell death, eventually resulting in brain secondary injury. In addition to neonatal HIBD, chloroquine (CQ) has been proved to exert a protective effect on BBB disruption in several brain injury models. The main purpose of this research was to study whether CQ protects the BBB from H/I insult and confers beneficial neuroprotection in the neonatal Rice-Vannucci rat model. Herein, we reported that CQ administration significantly reduced brain damage and improved behavioral dysplasia after H/I injury. Moreover, we demonstrated the protective effects of CQ on BBB integrity, evidenced by ameliorating brain edema and Evans blue extravasation, inhibiting the degeneration of the tight junction and adherens junction proteins, and improving pericyte survival in neonatal rats after HIBD. These findings indicated that CQ administration protected the BBB against H/I injury, thereby ameliorating brain damage and promoting neurofunctional recovery. Collectively, our data demonstrated that CQ played a crucial role in BBB integrity after neonatal H/I injury, which sheds light on the development of therapeutic agents to treat HIBD.

The Protection by Vitamin E Against Tramadol-Induced Proconvulsant Effects and Brain Damage in Pentylenetetrazole-Induced Status Epilepticus in Rats

We investigated the effect of the opioid analgesic tramadol on the development of epileptic seizures and neuronal injury and the possible modulatory effect of vitamin E (Vit E) in rats with pentylenetetrazole (PTZ)-induced status epilepticus. Rats received repeated intraperitoneal (i.p.) injections of PTZ till the development of status epilepticus and were pretreated once with tramadol (30, 60 or 90 mg/kg), vitamin E (Vit E, 70 mg/kg) or both tramadol (90 mg/kg) and Vit E (70 mg/kg) prior to starting PTZ injections. Seizure scores, the latency time and the PTZ dose for each group required to reach status epilepticus were determined and histopathological examination of the brain tissue was done. Results indicated that tramadol produced both anticonvulsant and proconvulsant effects. The anticonvulsant effects of tramadol were observed for facial twitching (stage 1), convulsive body waves (stage 2), and myoclonic jerks and rearing (stage 3) and turn over onto one side position (stage 4) that were significantly inhibited by tramadol. In contrast, tonic-clonic convulsions (stage 5) were significantly increased by 60 or 90 mg/kg of tramadol as compared to PTZ control group. The mean latency and PTZ threshold dose for status epilepticus were markedly decreased after tramadol. The administration of Vit E exerted beneficial effects in decreasing epilepsy scores and increasing both the latency time and threshold dose of PTZ for reaching status epilepticus. Meanwhile, rats treated with both tramadol and Vit E exhibited significant increase in tonic-clonic convulsions and markedly shortened latency time to reach status epilepticus compared to those treated with only Vit E. In cerebral cortex and hippocampus, PTZ resulted in apoptotic cells, darkly stained degenerated and vacuolated neurons and gliosis. These pathological changes increased after tramadol but were markedly reduced by Vit E treatment. Collectively, these results suggest that: (i) tramadol exerts both anticonvulsant and proconvulsant effects; (ii) tramadol shortened the latency time and decreased the threshold dose of PTZ for evoking status epilepticus; (iii) PTZ-induced seizures and brain damage can be inhibited by Vit E; (iv) tramadol at high doses interferes with the effect of Vit E in inhibiting tonic-clonic convulsions and in reducing brain damage.

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control.

The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline.