Astrocytes in functional recovery following central nervous system injuries.

Astrocytes are increasingly recognised as partaking in complex homeostatic mechanisms critical for regulating neuronal plasticity following central nervous system (CNS) insults. Ischaemic stroke and traumatic brain injury are associated with high rates of disability and mortality. Depending on the context and type of injury, reactive astrocytes respond with diverse morphological, proliferative and functional changes collectively known as astrogliosis, which results in both pathogenic and protective effects. There is a large body of research on the negative consequences of astrogliosis following brain injuries. There is also growing interest in how astrogliosis might in some contexts be protective and help to limit the spread of the injury. However, little is known about how astrocytes contribute to the chronic functional recovery phase following traumatic and ischaemic brain insults. In this review, we explore the protective functions of astrocytes in various aspects of secondary brain injury such as oedema, inflammation and blood-brain barrier dysfunction. We also discuss the current knowledge on astrocyte contribution to tissue regeneration, including angiogenesis, neurogenesis, synaptogenesis, dendrogenesis and axogenesis. Finally, we discuss diverse astrocyte-related factors that, if selectively targeted, could form the basis of astrocyte-targeted therapeutic strategies to better address currently untreatable CNS disorders.

Progress on siRNA-based gene therapy targeting secondary injury after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a life-threatening condition with a high mortality rate. For survivors, quality of life is determined by primary and secondary phases of injury. The prospects for injury repair and recovery after ICH are highly dependent on the extent of secondary injury. Currently, no effective treatments are available to prevent secondary injury or its long-term effects. One promising strategy that has recently garnered attention is gene therapy, in particular, small interfering RNAs (siRNA), which silence specific genes responsible for destructive effects after hemorrhage. Gene therapy as a potential treatment for ICH is being actively researched in animal studies. However, there are many barriers to the systemic delivery of siRNA-based therapy, as the use of naked siRNA has limitations. Recently, the Food and Drug Administration approved two siRNA-based therapies, and several are undergoing Phase 3 clinical trials. In this review, we describe the advancements in siRNA-based gene therapy for ICH and also summarize its advantages and disadvantages.

Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents.

OBJECTIVE: Neuroprotection is a precise target for the treatment of neurodegenerative diseases, ischemic stroke, and traumatic brain injury. Pyrimidine and its derivatives have been proven to use antiviral, anticancer, antioxidant, and antimicrobial activity prompting us to study the neuroprotection and anti-inflammatory activity of the triazole-pyrimidine hybrid on human microglia and neuronal cell model. METHODS: A series of novel triazole-pyrimidine-based compounds were designed, synthesized and characterized by mass spectra, 1HNMR, 13CNMR, and a single X-Ray diffraction analysis. Further, the neuroprotective, anti-neuroinflammatory activity was evaluated by cell viability assay (MTT), Elisa, qRT-PCR, western blotting, and molecular docking. RESULTS: The molecular results revealed that triazole-pyrimidine hybrid compounds have promising neuroprotective and anti-inflammatory properties. Among the 14 synthesized compounds, ZA3-ZA5, ZB2-ZB6, and intermediate S5 showed significant anti-neuroinflammatory properties through inhibition of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production in LPS-stimulated human microglia cells. From 14 compounds, six (ZA2 to ZA6 and intermediate S5) exhibited promising neuroprotective activity by reduced expression of the endoplasmic reticulum (ER) chaperone, BIP, and apoptosis marker cleaved caspase-3 in human neuronal cells. Also, a molecular docking study showed that lead compounds have favorable interaction with active residues of ATF4 and NF-kB proteins. CONCLUSION: The possible mechanism of action was observed through the inhibition of ER stress, apoptosis, and the NF-kB inflammatory pathway. Thus, our study strongly indicates that the novel scaffolds of triazole-pyrimidine-based compounds can potentially be developed as neuroprotective and anti-neuroinflammatory agents.

Sex differences in pregabalin-seeking like behavior in a conditioned place preference paradigm.

Substance abuse is a chronic, relapsing disorder characterized by compulsive drug use regardless of negative consequences. Incremental increases in pregabalin abuse have been observed in Saudi Arabia and throughout the world. In previous studies, the potential for pregabalin abuse with escalating doses of the drug (30, 60, 90, and 120 mg/kg) were investigated in male mice. Notably, researchers have argued that women may exhibit a greater tendency to consume drugs without a prescription to alleviate stress and depression. Moreover, female subjects are more prone to impulsivity in drug intake or abuse than their male counterparts. Therefore, in the present study, we compared the potential for pregabalin abuse between male and female mice using a conditioned place preference paradigm. Male and female BALB/c mice were divided into four groups based on the pregabalin dose administered (30, 60, 90, or 120 mg/kg, intraperitoneal). Preference scores were then calculated and compared between male and female mice in each dosage group. Interestingly, preference scores were significantly higher in female mice than in male mice at dosages of 30 and 120 mg/kg. These findings indicate that female mice may be more prone to pregabalin abuse and tolerance than male mice. These results might be helpful to the healthcare providers and policymakers to consider these sex differences in choosing therapeutic plans and consider alternatives to the misused prescription medications.

Tribulusterine Containing Tribulus terrestris Extract Exhibited Neuroprotection Through Attenuating Stress Kinases Mediated Inflammatory Mechanism: In Vitro and In Vivo Studies.

The present study has been aimed to explore the different secondary messengers of the inflammatory pathway NF-κB, kinases (JNK, P38MAPK, GSK3ß/ßcatenin), apoptosis pathway (Caspase-3 and AIF), and neuronal survival pathway (BDNF) in order to understand the neuroprotective mechanism of aqueous extract of Tribulus terrestris (AQTT). In primary cortical neurons, the ischemic condition was induced through oxygen-glucose deprivation (OGD). Anti-inflammatory activity of AQTT was evaluated in formalin induced inflammation model and carrageenan-induced paw edema test. The bilateral common carotid artery occlusion model was employed for whole animal studies. Treatment of AQTT (100 mg/kg) significantly reduced the inflammation induced by formalin and carrageenan. The neuroprotective mechanism of AQTT (50 and 100 mg/kg) was assessed by pre- and post-administration. The results indicate down regulation of kinases and NFkB, suggesting possible anti-inflammatory activity of AQTT. Additionally, AQTT down regulated both caspase dependent and independent apoptotic pathways suggesting its possible anti-apoptotic activity. The treatment of AQTT also reduced GSK3ß levels and increased p-Ser9 GSK3ß levels; stabilizing the unphosphorylated form of ß-catenin and its translocation into the nucleus suggesting role of AQTT in neuronal survival and GSK3ß mediated anti-inflammatory property. In comparison to pretreatment, post treatment of AQTT had lesser effects indicating tribulusterine standardized AQTT may have prophylactic effect. This study can be concluded with the thesis that AQTT has neuroprotective effect through alternating neuroinflammation, apoptosis, and promoting neuron survival. Being that it produced better effect with pretreatment, exploring this with thrombolytic drugs will be beneficial. For the first time AQTT has been reported for this indication.

A Bioactive Resveratrol Trimer from the Stem Bark of the Sri Lankan Endemic Plant Vateria copallifera.

A new resveratrol trimer, vateriferol (1), having four cis-oriented methine protons and constituting four contiguous stereocenters, was isolated from the bark extract of Vateria copallifera by bioassay-guided fractionation using a combination of normal, reversed phase, and size exclusion column chromatography. The structure was established based on its spectroscopic data. Vateriferol (1) was evaluated in vitro for its antioxidant capacity, enzyme inhibitory activity, growth inhibitory activity on a number of cancer cell lines, neuroprotective activity, and anti-inflammatory activity. Vateriferol (1) exhibited AChE inhibitory activity (IC50 8.4 ± 0.2 µM), ORAC activity (2079 ± 0.20 TE/g), and neuroprotective activity at 1.5 µM using PC12 cells deprived of oxygen and glucose and lowered NO levels in lipopolysaccharide-stimulated SIM-A9 microglial cells at 14.7 and 73.6 µM. Vateriferol (1) exhibited weak cytotoxic potency (<50% growth inhibition) against the tested cell lines at 147.2 µM.

Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique.

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.

Hyperchloremia and Hypernatremia Decreased Microglial and Neuronal Survival during Oxygen-Glucose Deprivation/Reperfusion.

Hyperchloremia and hypernatremia are associated with higher mortality in ischemic stroke, but it remains unclear whether their influence directly contributes to ischemic injury. We investigated the impact of 0.9% sodium chloride (154 mM NaCl), 0.9% sodium acetate (167 mM CH3COONa), and their different combinations (3:1, 2:1, and 1:1) on microglial (HMC-3) and neuronal (differentiated SH-SY5Y) survival during oxygen-glucose deprivation/reperfusion (OGD/R). Further, we assessed the effect of hyperchloremia and hypernatremia-treated and OGD/R-induced HMC-3-conditioned media on differentiated SH-SY5Y cells under OGD/R conditions. We performed cell viability, cell toxicity, and nitric oxide (NO) release assays and studied the alteration in expression of caspase-1 and caspase-3 in different cell lines when exposed to hyperchloremia and hypernatremia. Cell survival was decreased in 0.9% NaCl, 0.9% CH3COONa, combinations of HMC-3 and differentiated SH-SY5Y, and differentiated SH-SY5Y cells challenged with HMC-3-conditioned media under normal and OGD/R conditions. Under OGD/R conditions, differentiated SH-SY5Y cells were less likely to survive exposure to 0.9% NaCl. Expression of caspase-1 and caspase-3 in HMC-3 and differentiated SH-SY5Y cells was altered when exposed to 0.9% NaCl, 0.9% CH3COONa, and their combinations. A total of 0.9% NaCl and 0.9% CH3COONa and their combinations decreased the NO production in HMC-3 cells under normal and OGD/R conditions. Both hypernatremia and hyperchloremia reduced the survival of HMC-3 and differentiated SH-SY5Y cells under OGD/R conditions. Based on the OGD/R in vitro model that mimics human ischemic stroke conditions, it possibly provides a link for the increased death associated with hyperchloremia or hypernatremia in stroke patients.

The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy.

This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aß plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.

Cofilin Inhibitor Improves Neurological and Cognitive Functions after Intracerebral Hemorrhage by Suppressing Endoplasmic Reticulum Stress Related-Neuroinflammation.

Neuroinflammation after intracerebral hemorrhage (ICH) is a crucial factor that determines the extent of the injury. Cofilin is a cytoskeleton-associated protein that drives neuroinflammation and microglia activation. A novel cofilin inhibitor (CI) synthesized and developed in our lab has turned out to be a potential therapeutic agent for targeting cofilin-mediated neuroinflammation in an in vitro model of ICH and traumatic brain injury. The current study aims to examine the therapeutic potential of CI in a mouse collagenase model of ICH and examine the neurobehavioral outcomes and its mechanism of action. Male mice were subjected to intrastriatal collagenase injection to induce ICH, and sham mice received needle insertion. Various concentrations (25, 50, and 100 mg/kg) of CI were administered to different cohorts of the animals as a single intravenous injection 3 h following ICH and intraperitoneally every 12 h for 3 days. The animals were tested for neurobehavioral parameters for up to 7 days and sacrificed to collect brains for hematoma volume measurement, Western blotting, and immunohistochemistry. Blood was collected for cofilin, TNF-α, and IL-1ß assessments. The results indicated that 50 mg/kg CI improved neurological outcomes, reversed post-stroke cognitive impairment, accelerated hematoma resolution, mitigated cofilin rods/aggregates, and reduced microglial and astrocyte activation in mice with ICH. Microglia morphological analysis demonstrated that CI restored the homeostasis ramification pattern of microglia in mice treated with CI. CI suppressed endoplasmic reticulum stress-related neuroinflammation by inhibiting inflammasomes and cell death signaling pathways. We also showed that CI prevented synaptic loss by reviving the pre- and post-synaptic markers. Our results unveil a novel therapeutic approach to treating ICH and open a window for using CI in clinical practice.

Natural products inspired synthesis of neuroprotective agents against H2O2-induced cell death.

Stroke is a debilitating disease and the third leading cause of death in the USA, where over 2000 new stroke cases are diagnosed every day. Treatment options for stroke-related brain damage are very limited and there is an urgent need for effective neuroprotective agents to treat these conditions. Comparison of the structures of several classes of neuroprotective natural products such as limonoids and cardiac glycosides revealed the presence of a common structural motif which may account for their observed neuroprotective activity. Several natural product mimics that incorporate this shared structural motif were synthesized and were found to possess significant neuroprotective activity. These compounds enhanced cell viability against H(2)O(2) induced oxidative stress or cell death in PC12 neuronal cells. The compounds were also found to enhance and modulate Na(+)/K(+)-ATPase activity of PC12 cells, which may suggest that the observed neuroprotective activity is mediated, at least partly, through interaction with Na(+)/K(+)-ATPase.

Development and validation of LC-MS/MS method for determining the metabolic stability, pharmacokinetics, and dose proportionality of a novel anti-inflammatory cofilin inhibitor.

A novel small molecule cofilin inhibitor (SZ-3) has recently become the focus of investigation for targeting neuroinflammation in different neurodegenerative diseases. In the present study, the metabolic stability, blood-brain barrier (BBB) penetration, and tissue concentration of SZ-3 were evaluated to support our future studies. In silico drug metabolism prediction was investigated using the StarDrop WhichP450 module. LC-MS/MS method was developed and validated to quantify the SZ-3 for in-vitro and in-vivo studies. The in-vitro metabolic stability was performed using human liver microsomes (HLMs), and the in-vivo pharmacokinetics were investigated in mice after a single intraperitoneal (IP) injection or oral (P.O.) administration, followed by a collection of blood and brain samples at different time points. The dose-proportionality was also evaluated after a single IP injection of three ascending doses (5, 10, and 25 mg/kg). In-vitro results showed that SZ-3 has a moderate intrinsic clearance (Clint) value of 17.42 ml/min/mg with a half-life (t1/2) value of 39.77 mins, indicative of good bioavailability. In vivo study revealed that SZ-3 was rapidly absorbed, entered the brain, and yielded a good concentration of the unbound drug after IP and oral administration. However, the higher maximum concentration (Cmax) values of IP and P.O. (2244 ng/ml and 1069 ng/g, respectively) revealed that the IP administration led to higher blood and brain concentrations than the P.O. Furthermore, Cmax and area under the curve (AUC) of SZ-3 increased in a dose-proportional manner between the three ascending doses. These results will guide us in optimizing the dosing regimen for future SZ-3 pharmacological studies targeting neuroinflammation.

The ER chaperone, BIP protects Microglia from ER stress-mediated Apoptosis in Hyperglycemia.

A major endoplasmic reticulum (ER) chaperone, binding of Immunoglobulin heavy chain protein (BIP) facilitates the assembly of newly synthesized proteins in the ER. Microglia vigorously respond to brain injuries and eliminate the damaged neuronal and apoptotic cells through phagocytosis in the central nervous system. However, the mechanism of BIP-mediated microglial function is not clear in hyperglycemia. We explored the molecular mechanism of BIP in microglial function during hyperglycemic conditions. Hyperglycemia was induced in mice by two consecutive intraperitoneal injections of streptozotocin (STZ 100/kg) and confirmed by measuring the blood glucose from day 2 to day 14. After 14 days of experimental hyperglycemia, mice were sacrificed and brains were collected for ER chaperone expression. In-vitro hyperglycemia was induced by exposing HMC3 cells to 25 mM glucose for 5 days and proteins involved in ER stress, apoptosis, and autophagy were analyzed. In hyperglycemic conditions, BIP protein expression was dramatically reduced in HMC3 cells, which led to increased apoptosis through the activation of CHOP and mitochondrial pro-apoptotic proteins (Bax, Bad, and cleaved caspase-3). The flow cytometry results indicate hyperglycemia-induced apoptosis and reactive oxygen species (ROS) production. Interestingly, the BIP inducer X restored the apoptosis in HMC3 cells by derepressing BIP expression and inhibiting ER stress. These results suggest that the ER chaperone BIP is required for the microglial function and protects from apoptosis in hyperglycemia. A better understanding of BIP's molecular mechanism and role in microglial function may contribute to developing novel therapies for microglia dysfunction-associated neurodegenerative diseases.

Spatiotemporal Cofilin Signaling, Microglial Activation, Neuroinflammation, and Cognitive Impairment Following Hemorrhagic Brain Injury.

Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-ß TGF-ß, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.

Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation.

Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro H2O2-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with H2O2 increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated H2O2-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against H2O2-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage.

Behavioural, genomics and proteomic approach to examine Alzheimer's disease in zebrafish.

Globally around 24 million elderly population are dealing with dementia, and this pathological characteristic is commonly seen in people suffering from Alzheimer's disease (AD). Despite having multiple treatment options that can mitigate AD symptoms, there is an imperative call to advance our understanding of the disease pathogenesis to unfold disease-modifying treatments/therapies. To explore the driving mechanisms of AD development, we stretch out further to study time-dependant changes after Okadaic acid (OKA)-induced AD-like conditions in zebrafish. We evaluated the pharmacodynamics of OKA at two-time points, i.e., after 4-days and 10-days exposure to zebrafish. T-Maze was utilized to observe the learning and cognitive behaviour, and inflammatory gene expressions such as 5-Lox, Gfap, Actin, APP, and Mapt were performed in zebrafish brains. To scoop everything out from the brain tissue, protein profiling was performed using LCMS/MS. Both time course OKA-induced AD models have shown significant memory impairment, as evident from T-Maze. Gene expression studies of both groups have reported an overexpression of 5-Lox, GFAP, Actin, APP, and OKA 10D group has shown remarkable upregulation of Mapt in zebrafish brains. In the case of protein expression, the heatmap suggested an important role of some common proteins identified in both groups, which can be explored further to investigate their mechanism in OKA-induced AD pathology. Presently, the preclinical models available to understand AD-like conditions are not completely understood. Hence, utilizing OKA in the zebrafish model can be of great importance in understanding the pathology of AD progression and as a screening tool for drug discovery.

Stroke: Molecular mechanisms and therapies: Update on recent developments.

Stroke, a neurological disease, is one of the leading causes of death worldwide, resulting in long-term disability in most survivors. Annual stroke costs in the United States alone were estimated at $46 billion recently. Stroke pathophysiology is complex, involving multiple causal factors, among which atherosclerosis, thrombus, and embolus are prevalent. The molecular mechanisms involved in the pathophysiology are essential to understanding targeted drug development. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress, and neuroinflammation. In addition, various modifiable and non-modifiable risk factors increase the chances of stroke manifolds. Once a patient encounters a stroke, complete restoration of motor ability and cognitive skills is often rare. Therefore, shaping therapeutic strategies is paramount for finding a viable therapeutic agent. Apart from tPA, an FDA-approved therapy that is applied in most stroke cases, many other therapeutic strategies have been met with limited success. Stroke therapies often involve a combination of multiple strategies to restore the patient's normal function. Certain drugs like Gamma-aminobutyric receptor agonists (GABA), Glutamate Receptor inhibitors, Sodium, and Calcium channel blockers, and fibrinogen-depleting agents have shown promise in stroke treatment. Recently, a drug, DM199, a recombinant (synthetic) form of a naturally occurring protein called human tissue kallikrein-1 (KLK1), has shown great potential in treating stroke with fewer side effects. Furthermore, DM199 has been found to overcome the limitations presented when using tPA and/or mechanical thrombectomy. Cell-based therapies like Neural Stem Cells, Hematopoietic stem cells (HSCs), and Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) are also being explored as a treatment of choice for stroke. These therapeutic agents come with merits and demerits, but continuous research and efforts are being made to develop the best therapeutic strategies to minimize the damage post-stroke and restore complete neurological function in stroke patients.

Use of mesenchymal stem cell therapy in COVID-19 related strokes.

Coronavirus disease 2019 (COVID-19) has affected a broad demographics, eliciting a more significant effect on specific groups such as males, African Americans, and Hispanic minorities. Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies. However, immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19. Mesenchymal stem cell therapy offers regenerative, anti-inflammatory, and immunomodulatory properties that can speed up the recovery from COVID-19. Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from strokes, as COVID-19 increases the risk of strokes due to increased cytokines and clotting factors. Most stroke cases that occur in COVID-19 patients are ischemic strokes. Therefore, with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes, COVID-19-induced stroke patients might benefit from dual-ended treatment. The objective of this review was to discuss COVID-19 and stroke incidence and the available treatment options.

Neuroprotection or Sex Bias: A Protective Response to Traumatic Brain Injury in the Females

Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and long-term outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.

Neuroprotective Potential of Flavonoids in Brain Disorders.

Flavonoids are a large subgroup of polyphenols known to be sourced from over 6000 natural products, including fruits, vegetables, bark, and herbs. Due to their antioxidant properties, flavonoids have been implicated as a therapy source for many diseases and conditions, including inflammation, vasculitis, venous insufficiency, and hemorrhoids. Currently, some flavonoids are being researched for their antioxidant ability concerning neuroprotection. These flavonoids can penetrate the blood-brain barrier and, depending on the specific flavonoid, retain adequate bioavailability in certain brain regions. Further data suggest that flavonoids could have a strong anti-inflammatory effect in the brain, which not only could be a robust therapeutic source for known neuroinflammatory diseases such as Alzheimer's Disease or Parkinson's Disease but also could be a therapeutic source for ischemic or hemorrhagic conditions such as a stroke. While flavonoid toxicity exists, they are relatively safe and non-invasive drugs from natural origins. As such, exploring the known mechanisms and therapies may highlight and establish flavonoid therapy as a viable source of therapy for stroke patients. As stated, many flavonoids are already being isolated, purified, and implemented in both in vitro and in vivo experiments. As these flavonoids proceed to clinical trials, it will be important to understand how they function as a therapy, primarily as antioxidants, and by other secondary mechanisms. This review aims to elucidate those mechanisms and explore the neuroprotective role of flavonoids.