Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Nanotechnology approaches to drug delivery for the treatment of ischemic stroke.

Ischemic stroke is a major global public health concern that lacks effective treatment options. A significant challenge lies in delivering therapeutic agents to the brain due to the restrictive nature of the blood-brain barrier (BBB). The BBB's selectivity hampers the delivery of therapeutically relevant quantities of agents to the brain, resulting in a lack of FDA-approved pharmacotherapies for stroke. In this article, we review therapeutic agents that have been evaluated in clinical trials or are currently undergoing clinical trials. Subsequently, we survey strategies for synthesizing and engineering nanoparticles (NPs) for drug delivery to the ischemic brain. We then provide insights into the potential clinical translation of nanomedicine, offering a perspective on its transformative role in advancing stroke treatment strategies. In summary, existing literature suggests that drug delivery represents a major barrier for clinical translation of stroke pharmacotherapies. While nanotechnology has shown significant promise in addressing this challenge, further advancements aimed at improving delivery efficiency and simplifying formulations are necessary for successful clinical translation.

Ulinastatin modulates NLRP3 inflammasome pathway in PTZ-induced epileptic mice: A potential mechanistic insight.

Objective: The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome-driven immune-inflammatory response has been shown to play a critical role in epilepsy progression across multiple studies. While Ulinastatin (UTI), an immunomodulatory agent known to target the NLRP3 pathway in neurological disorders, its implications in epilepsy have not been extensively studied. This investigation aims to explore UTI's role and underlying mechanisms in epilepsy. Methods: To assess UTI's effects on epilepsy severity, neuroinflammation, and BBB integrity, a pentylenetetrazole (PTZ)-induced epilepsy model in mice and a co-culture system involving BV2 and HT22 cells stimulated by lipopolysaccharide (LPS) and ATP were employed. Techniques utilized included qPCR, Western blotting, ELISA, immunohistochemistry (IHC) staining, Evans Blue dye extravasation, glutamate assays, the Morris water maze, and Annexin V apoptosis assays. Results: In the PTZ model, UTI administration led to a substantial decrease in seizure intensity and susceptibility, inhibited NLRP3 inflammasome activation, reduced neuroinflammatory interactions, lowered hippocampal and systemic inflammatory mediator levels, and improved cognitive performance. Furthermore, UTI upregulated claudin-5 expression, a tight junction protein in the endothelium, and diminished Evans Blue dye leakage, indicating improved BBB integrity. In BV2 and HT22 cell co-culture models, UTI exerted neuroprotective effects by mitigating microglia-mediated neurotoxicity and fostering neuronal recovery. Conclusions: The findings demonstrate that UTI exerts transformative regulatory effects on the NLRP3 inflammasome in epilepsy models. This intervention effectively suppresses neuroinflammation, lessens seizure severity and susceptibility, and ameliorates epilepsy-related BBB dysfunction and cognitive impairments.

Sex-dependent temporal changes in astrocyte-vessel interactions following diffuse traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5-6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology.

Engineered 3D human neurovascular model of Alzheimer's disease to study vascular dysfunction.

The blood-brain barrier (BBB) serves as a selective filter that prevents harmful substances from entering the healthy brain. Dysfunction of this barrier is implicated in several neurological diseases. In the context of Alzheimer's disease (AD), BBB breakdown plays a significant role in both the initiation and progression of the disease. This study introduces a three-dimensional (3D) self-assembled in vitro model of the human neurovascular unit to recapitulate some of the complex interactions between the BBB and AD pathologies. It incorporates primary human brain endothelial cells, pericytes and astrocytes, and stem cell-derived neurons and astrocytes harboring Familial AD (FAD) mutations. Over an extended co-culture period, the model demonstrates increased BBB permeability, dysregulation of key endothelial and pericyte markers, and morphological alterations mirroring AD pathologies. The model enables visualization of amyloid-beta (Aß) accumulation in both neuronal and vascular compartments. This model may serve as a versatile tool for neuroscience research and drug development to provide insights into the dynamic relationship between vascular dysfunction and AD pathogenesis.

GLP-1 programs the neurovascular landscape.

Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.

Neuroinflammation and blood-brain barrier breakdown in acute, clinical intracerebral hemorrhage.

Neuroinflammation is a promising therapeutic target in intracerebral hemorrhage (ICH), characterized in the brain by microglial activation and blood-brain barrier (BBB) breakdown. In this study, 36 acute, spontaneous, supratentorial ICH patients underwent dynamic contrast-enhanced MRI to measure BBB permeability (Ktrans) 1-3 days post-onset and 16 returned for [11C](R)-PK11195 PET to quantify microglial activation (BPND), 2-7 days post-onset. We first tested if these markers were increased and co-localized in the perihematomal brain and found that perihematomal Ktrans and BPND were increased vs. the contralateral brain, but regions of high Ktrans and BPND only overlapped by a mean of 4.9%. We then tested for associations of perihematomal Ktrans and BPND with clinical characteristics (age, ICH volume & location, blood pressure), other markers of inflammation (edema, IL-6, and CRP), and long-term functional outcome (90-day mRS). Lower perihematomal BPND was associated with increasing age. Lobar hemorrhage was associated with greater Ktrans than deep, but Ktrans and BPND were not associated with ICH volume, or other inflammatory markers. While perihematomal Ktrans and BPNDwere not associated with outcome, contralateral Ktrans was significantly associated with greater 90-day mRS. Exploratory analyses demonstrated that blood pressure variability over 72 h was also associated with contralateral Ktrans.

Omega-3 Polyunsaturated Fatty Acids and Blood-Brain Barrier Integrity in Major Depressive Disorder: Restoring Balance for Neuroinflammation and Neuroprotection.

Major depressive disorder (MDD), affecting over 264 million individuals globally, is associated with immune system dysregulation and chronic neuroinflammation, potentially linked to neurodegenerative processes. This review examines blood-brain barrier (BBB) dysfunction in MDD, focusing on key regulators like matrix metalloproteinase 9 (MMP9), aquaporin-4 (AQP4), and ATP-binding cassette subfamily B member 1 (ABCB1). We explore potential mechanisms by which compromised BBB integrity in MDD may contribute to neuroinflammation and discuss the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs). n-3 PUFAs have demonstrated anti-inflammatory and neuroprotective effects, and potential ability to modulate MMP9, AQP4, and ABCB1, thereby restoring BBB integrity in MDD. This review aims to elucidate these potential mechanisms and evaluate the evidence for n-3 PUFAs as a strategy to mitigate BBB dysfunction and neuroinflammation in MDD.

Association between risk of Alzheimer's disease and related dementias and angiotensin receptor â ¡ blockers treatment for individuals with hypertension in high-volume claims data.

BACKGROUND: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. METHODS: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. FINDINGS: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P < 0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P < 0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P < 0.0001). INTERPRETATION: This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings. FUNDING: This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604).

CMUT for ultrafast passive cavitation detection during ultrasound-induced blood-brain barrier disruption: proof of concept study.

OBJECTIVE: Cavitation dose monitoring plays a key role in ultrasound drug delivery to the brain. The use of CMUT technology has a great potential for passive cavitation detection (PCD). Approach. Here, a circular (diameter 7mm) capacitive micromachined ultrasonic transducer (CMUT) centered at 5MHz was designed to be inserted into a therapeutic transducer (1.5MHz) used for ultrasound-induced blood-brain barrier (BBB) disruption on mice. CMUT-based real-time cavitation detection was performed during the ultrasound procedure (50µL intravenous injection of SonoVue microbubbles, Frequency 1.5MHz, PNP 480kPa, Duty Cycle 10%, PRF 10Hz, Duration 60s). BBB disruption were confirmed by contrast-enhanced 7T-MRI. Main results. The CMUT device has a fractional bandwidth of 140%, almost twice a conventional piezocomposite PCD transducer. As expected, the CMUT device was able to detect the occurrence of harmonic, subharmonic and ultraharmonic frequencies as well as the increase of broadband signal indicating inertial cavitation in a wide frequency range (from 0.75 to 6 MHz). Signal-to-noise ratio was high enough (> 40 dB) to perform ultrafast monitoring and follow the subtle intrapulse variations of frequency components at a rate of 10 kHz. Significance. This first in vivo proof of concept demonstrates the interest of CMUT for PCD and encourages us to develop devices for PCD in larger animals by integrating an amplifier directly to the CMUT front-end to considerably increase the signal-to-noise ratio.

Salidroside improves blood-brain barrier integrity and cognitive function in hypobaric hypoxia mice by inhibiting microglia activation through GSK3ß.

Salidroside, an active component found in Rhodiola rosea L., has emerged as a potential therapeutic agent for the prevention and treatment of hypoxic brain injury, while the precise target and mechanism of salidroside were remain unclear. The study utilized techniques such as network pharmacology, transcriptome sequencing to investigate the mechanism and target of salidroside in regulating blood-brain barrier (BBB) function to protect hypoxic brain injury in vivo. Utilized macromolecular docking and molecular biology techniques to explore the molecular mechanism of salidroside in alleviating brain injury induced by hypoxia in BV2 cell model. The results show that salidroside alleviated the learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia, reduced brain water content and attenuate the inflammatory response and oxidative stress, effectively reversed S100ß in serum and promoted the repair of BBB. GSK3ß is an important therapeutic target of salidroside in the treatment of hypoxic cognitive impairment, and salidroside can specifically bind GSK3ß in the ATP binding pocket, inducing the phosphorylation of GSK3ß, targeting downstream Nrf-2 to regulate microglia activity, promoting the accumulation of ß-catenin, thereby inhibiting microglial activation, improving the BBB integrity injury and achieving a neuroprotective effect. This study demonstrates that salidroside can inhibit the activation of microglia by inducing GSK3ß phosphorylation, achieve neuroprotective effects and alleviate learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development of salidroside and the clinical application of Rhodiola rosea L.

Utilizing Multifaceted Approaches to Target Drug Delivery in the Brain: From Nanoparticles to Biological Therapies.

The blood-brain barrier (BBB) poses an important obstacle to treating neurological disorders because it limits the entry of therapeutic agents into the central nervous system (CNS). Surmounting this barrier is crucial for delivering drugs effectively and targeting precise areas of the brain affected by conditions like Parkinson's disease, Alzheimer's disease, and brain tumors. This review examines the diverse strategies employed to enhance brain targeting, including nanotechnology, viral vectors, and biological therapies. Nanoparticles, liposomes, and dendrimers offer promising approaches for encapsulating drugs and facilitating their transport across the BBB. Viral vectors, such as adeno-associated viruses, demonstrate high transfection efficiency for gene therapy applications in CNS diseases. Biological therapies, including stem cell transplantation and neuromodulation techniques, can potentially restore normal cellular function and treat genetic disorders. Challenges such as BBB permeability, safety concerns, and regulatory considerations are discussed, along with future perspectives on precision medicine, noninvasive delivery methods, and biomarker discovery. By addressing these challenges and embracing innovative approaches, the field of brain drug targeting aims to transfer the way that neurological illness is treated and improve patient outcomes.

Single domain antibody-scFv conjugate targeting amyloid ß and TfR penetrates the blood-brain barrier and interacts with amyloid ß.

Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.

Drug-Induced Mitochondrial Disruption in the Blood-Brain Barrier Cells: Overlooked Player in Drug Safety Evaluation.

The blood-brain barrier (BBB) is based on the unique pattern of the microvasculature of the central nervous system (CNS), which controls the transport of molecules between the CNS and the blood. The blood-brain barrier is mainly composed of endothelial cells, pericytes, and basement membrane, as well as the astrocytes and immune cells as perivascular macrophages and microglial cells. The dysfunction of this barrier can cause serious neuronal disorders due to the transport of hazardous molecules and immune cells to the CNS. Mitochondria plays a major role in cellular homeostasis in terms of health and disease. This review evaluated the published data about the effect of the drugs on the cells of BBB. Only seven articles were found that considered the effect of drugs on the barrier endothelial cells and mitochondria via different assays. Further studies are recommended to evaluate the impact of used medications on BBB cell bioenergetics. Also, the effect of the newly studied pharmaceutical agents on the BBB bioenergetics should be included within their safety profile studies.

Association Between Blood-Brain Barrier Disruption and Stroke-Associated Pneumonia in Acute Ischemic Stroke Patients After Endovascular Therapy: A Retrospective Cohort Study.

Background: Stroke, particularly due to large vessel occlusion (LVO), is a major cause of mortality and disability globally. Endovascular therapy (ET) significantly improves outcomes for acute ischemic stroke (AIS) patients, but complications such as stroke-associated pneumonia (SAP) increase mortality and healthcare costs. This study investigates the association between blood-brain barrier (BBB) disruption and the increased risk of SAP and explores the relationship between BBB disruption and medium-term functional outcomes. Methods: The retrospective cohort study was performed on AIS patients enrolled between January 2019 to February 2023 who underwent ET. Patients were divided into two groups: BBB disruption and without BBB disruption. Multiple logistic regression model was conducted to measure the association between BBB disruption and SAP. Mediation analysis was used to estimate the potential mediation effects on the associations of BBB disruption with SAP. A restricted cubic spline (RCS) regression model was used to further outline the connection between the highest CT value of hyperattenuated lesions areas and the risk of SAP. Results: The study included 254 patients who underwent endovascular therapy, with 155 patients in the BBB disruption group (exposure) and 99 patients in the without BBB disruption group (control). Multiple logistic regression analysis revealed a significantly increased risk of SAP in patients with BBB disruption (OR = 2.337, 95% CI: 1.118-4.990, p = 0.025). Furthermore, mediation analysis suggested that this association may be partly due to malignant cerebral oedema and haemorrhagic transformation. The study found an inverse L-shaped dose-response relationship between the maximum CT values of BBB disruption areas and the incidence of SAP. SAP partially mediated the association between BBB disruption and 3-month poor functional outcome. Conclusion: BBB disruption are a potential risk factor for SAP. BBB disruption may affect short- and medium-term prognosis of patients after ET in part through SAP.

Nanosystems for targeted drug Delivery: Innovations and challenges in overcoming the Blood-Brain barrier for neurodegenerative disease and cancer therapy.

The evolution of sophisticated nanosystems has revolutionized biomedicine, notably in treating neurodegenerative diseases and cancer. These systems show potential in delivering medication precisely to affected tissues, improving treatment effectiveness while minimizing side effects. Nevertheless, a major hurdle in targeted drug delivery is breaching the blood-brain barrier (BBB), a selective shield separating the bloodstream from the brain and spinal cord. The tight junctions between endothelial cells in brain capillaries create a formidable physical barrier, alongside efflux transporters that expel harmful molecules. This presents a notable challenge for brain drug delivery. Nanosystems present distinct advantages in overcoming BBB challenges, offering enhanced drug efficacy, reduced side effects, improved stability, and controlled release. Despite their promise, challenges persist, such as the BBB's regional variability hindering uniform drug distribution. Efflux transporters can also limit therapeutic agent efficacy, while nanosystem toxicity necessitates rigorous safety evaluations. Understanding the long-term impact of nanomaterials on the brain remains crucial. Additionally, addressing nanosystem scalability, cost-effectiveness, and safety profiles is vital for widespread clinical implementation. This review delves into the advancements and obstacles of advanced nanosystems in targeted drug delivery for neurodegenerative diseases and cancer therapy, with a focus on overcoming the BBB.

The evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies.

Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.

Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury.

Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.

Hypoxia-Induced Inflammation in In Vitro Model of Human Blood-Brain Barrier: Modulatory Effects of the Olfactory Ensheathing Cell-Conditioned Medium.

Hypoxia compromises the integrity of the blood-brain barrier (BBB) and increases its permeability, thereby inducing inflammation. Olfactory ensheathing cells (OECs) garnered considerable interest due to their neuroregenerative and anti-inflammatory properties. Here, we aimed to investigate the potential modulatory effects of OEC-conditioned medium (OEC-CM) on the response of human brain microvascular endothelial cells (HBMECs), constituting the BBB, when exposed to hypoxia. HBMECs were utilized to establish the in vitro BBB model. OECs were isolated from mouse olfactory bulbs, and OEC-CM was collected after 48 h of culture. The effect of OEC-CM treatment on the HBMEC viability was evaluated under both normoxic and hypoxic conditions at 6 h, 24 h, and 30 h. Western blot and immunostaining techniques were employed to assess NF-κB/phospho-NF-κB expression. HIF-1α, VEGF-A, and cPLA2 mRNA expression levels were quantified using digital PCR. ELISA assays were performed to measure PGE2, VEGF-A, IL-8 secretion, and cPLA2 specific activity. The in vitro formation of HBMEC capillary-like structures was examined using a three-dimensional matrix system. OEC-CM attenuated pro-inflammatory responses and mitigated the HIF-1α/VEGFA signaling pathway activation in HBMECs under hypoxic condition. Hypoxia-induced damage of the BBB can be mitigated by novel therapeutic strategies harnessing OEC potential.