Methylene Blue Pretreatment Protects Against Repeated Neonatal Isoflurane Exposure-Induced Brain Injury and Memory Loss.

Perioperative neurocognitive impairment (PND) is a common medical complication in the postoperative period. General anesthesia through volatile anesthetics poses a high risk of POCD. Moreover, the developing brain is especially vulnerable to anesthesia-induced neurotoxicity. Therefore, finding a practical approach to prevent or alleviate neonatal isoflurane (ISO) exposure-induced brain injury and cognitive decline is essential for reducing medical complications following major surgery during the early postnatal period. Using a repeated neonatal ISO exposure-induced PND rat model, we investigated the effects of methylene blue (MB) pretreatment on repeated neonatal isoflurane exposure-induced brain injury and memory loss. Intraperitoneal injection of low-dose MB (1 mg/kg) was conducted three times 24 h before each ISO exposure. The Barnes maze and novel objection test were conducted to assess learning and memory. Immunofluorescence staining, F-Jade C staining, TUNEL staining, and Western blot analysis were performed to determine mitochondrial fragmentation, neuronal injury, degeneration, and apoptosis. Evans blue extravasation assay, total antioxidant capacity assay, MDA assay kit, and related inflammatory assay kits were used to test blood-brain barrier (BBB) disruption, antioxidant capacity, and neuroinflammation. Behavioral tests revealed that MB pretreatment significantly ameliorated ISO exposure-induced cognitive deficits. In addition, MB pretreatment alleviates neuronal injury, apoptosis, and degeneration. Furthermore, the BBB integrity was preserved by MB pretreatment. Additional studies revealed that ISO-induced excessive mitochondrial fragmentation, oxidative stress, and neuroinflammation were significantly attenuated by MB pretreatment in the PND rat model. Our findings suggest that MB pretreatment alleviates ISO exposure-induced brain injury and memory loss for the first time, supporting MB pretreatment as a promising approach to protect the brain against neonatal ISO exposure-induced postoperative cognitive dysfunction.

Photobiomodulation therapy alleviates repeated closed head injury-induced anxiety-like behaviors.

Repeated closed head injury (rCHI) is one of the most common brain injuries. Although extensive studies have focused on how to treat rCHI-induced brain injury and reduce the possibility of developing memory deficits, the prevention of rCHI-induced anxiety has received little research attention. The current study was designed to assess the effects of photobiomodulation (PBM) therapy in preventing anxiety following rCHI. The rCHI disease model was constructed by administering three repeated closed-head injuries within an interval 5 days. 2-min daily PBM therapy using an 808 nm continuous wave laser at 350 mW/cm2 on the scalp was implemented for 20 days. We found that PBM significantly ameliorated rCHII-induced anxiety-like behaviors, neuronal apoptosis, neuronal injury, promotes astrocyte/microglial polarization to anti-inflammatory phenotype, preserves mitochondrial fusion-related protein MFN2, attenuates the elevated mitochondrial fission-related protein DRP1, and mitigates neuronal senescence. We concluded that PBM therapy possesses great potential in preventing anxiety following rCHI.

Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology.

Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood-brain barrier (BBB). However, under the pathological circumstances of Alzheimer's disease (AD), the brain's microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.

Microglia and Astrocytes in Alzheimer's Disease: Significance and Summary of Recent Advances.

Alzheimer's disease, one of the most common forms of dementia, is characterized by a slow progression of cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered by various side effects and limited efficacy. Despite considerable research, practical treatments for AD have not been developed. Increasing evidence shows that glial cells, especially microglia and astrocytes, are essential in the initiation and progression of AD. During AD progression, activated resident microglia increases the ability of resting astrocytes to transform into reactive astrocytes, promoting neurodegeneration. Extensive clinical and molecular studies show the involvement of microglia and astrocyte-mediated neuroinflammation in AD pathology, indicating that microglia and astrocytes may be potential therapeutic targets for AD. This review will summarize the significant and recent advances of microglia and astrocytes in the pathogenesis of AD in three parts. First, we will review the typical pathological changes of AD and discuss microglia and astrocytes in terms of function and phenotypic changes. Second, we will describe microglia and astrocytes' physiological and pathological role in AD. These roles include the inflammatory response, "eat me" and "don't eat me" signals, Aß seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, and demyelination. Last, we will review the pharmacological and non-pharmacological therapies targeting microglia and astrocytes in AD. We conclude that microglia and astrocytes are essential in the initiation and development of AD. Therefore, understanding the new role of microglia and astrocytes in AD progression is critical for future AD studies and clinical trials. Moreover, pharmacological, and non-pharmacological therapies targeting microglia and astrocytes, with specific studies investigating microglia and astrocyte-mediated neuronal damage and repair, may be a promising research direction for future studies regarding AD treatment and prevention.

Exogenous lactate administration: A potential novel therapeutic approach for neonatal hypoxia-ischemia.

Neonatal hypoxic-ischemic encephalopathy (HIE) is the primary reason for neonatal mortality and prolonged disablement. Currently, hypothermia is the only approved clinical treatment available for HIE. However, hypothermia's limited therapeutic efficacy and adverse effects suggest an urgent need to advance our knowledge of its molecular pathogenesis and develop novel therapies. The leading cause of HIE is impaired cerebral blood flow and oxygen deprivation-initiated primary and secondary energy failure. Lactate was traditionally regarded as a marker of energy failure or a waste product of anaerobic glycolysis. Recently, the beneficial aspects of lactate as supplementary energy for neurons have been demonstrated. Under the conditions of HI, lactate supports various functions of neuronal cells, including learning and memory formation, motor coordination, and somatosensory. Furthermore, lactate contributes to the regeneration of blood vessels and has shown its beneficial effects on the immune system. This review first introduces the hypoxic or ischemic events-induced fundamental pathophysiological changes in HIE and then discusses the potential neuroprotective properties of lactate for the treatment and prevention of HIE. Finally, we discuss the possible protective mechanisms of lactate in the context of the pathological features of perinatal HIE. We conclude that exogenous and endogenous lactate exert neuroprotective effects in HIE. Lactate administration may be a potential approach to treating HIE injury.

High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization.

Background: Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aß accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD. The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aß and abnormal tau clearance and is a potential therapeutic target for AD. However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood. Methods: Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies. The Branes maze task was conducted to measure spatial learning and memory. Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage. Sholl analysis was carried out to analyze the morphology of microglia. Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aß, respectively. An APP/PS1 transgenic AD mice model was used to confirm the key findings. Results: High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss. Additionally, HIIT improved the drainage of abnormal tau and Aß from the cortex and hippocampus via the glymphatic system to the kidney. Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype. Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype. We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Conclusion: Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization. These changes promote Aß and p-tau clearance from the brain tissue through the glymphatic system and the kidney.

Neuroprotective Effect of Sub-lethal Hyperthermia Preconditioning in a Rat Model of Repeated Closed Head Injury.

Repeated mild traumatic brain injury (rTBI), one of the most common forms of traumatic brain injury, is a worldwide severe public health concern. rTBI induces cumulative neuronal injury, neurological dysfunction, and cognitive deficits. Although there are clinical treatment methods, there is still an urgent need to develop preventive approaches for susceptible populations. Using a repeated closed head injury (rCHI) rat model, we interrogate the effect of sub-lethal hyperthermia preconditioning (SHP) on rCHI-induced neuronal injury and behavioral changes. Our study applied the repeated weight-drop model to induce the rCHI. According to the changes of heat shock protein 70 (HSP 70) in the cortex and hippocampus following a single SHP treatment in normal rats, the SHP was delivered to the rats 18 h before rCHI. We found that HSP significantly alleviated rCHI-induced anxiety-like behaviors and impairments in motor abilities and spatial memory. SHP exerts significant neuroprotection against rCHI-induced neuronal damage, apoptosis, and neuroinflammation. Our findings support the potential use of SHP as a preventative approach for alleviating rCHI-induced brain damage.

Molecular Hydrogen: an Emerging Therapeutic Medical Gas for Brain Disorders.

Oxidative stress and neuroinflammation are the main physiopathological changes involved in the initiation and progression of various neurodegenerative disorders or brain injuries. Since the landmark finding reported in 2007 found that hydrogen reduced the levels of peroxynitrite anions and hydroxyl free radicals in ischemic stroke, molecular hydrogen's antioxidative and anti-inflammatory effects have aroused widespread interest. Due to its excellent antioxidant and anti-inflammatory properties, hydrogen therapy via different routes of administration exhibits great therapeutic potential for a wide range of brain disorders, including Alzheimer's disease, neonatal hypoxic-ischemic encephalopathy, depression, anxiety, traumatic brain injury, ischemic stroke, Parkinson's disease, and multiple sclerosis. This paper reviews the routes for hydrogen administration, the effects of hydrogen on the previously mentioned brain disorders, and the primary mechanism underlying hydrogen's neuroprotection. Finally, we discuss hydrogen therapy's remaining issues and challenges in brain disorders. We conclude that understanding the exact molecular target, finding novel routes, and determining the optimal dosage for hydrogen administration is critical for future studies and applications.

Estrogen receptors mediate the antidepressant effects of aerobic exercise: A possible new mechanism.

Purpose: This study aimed to examine whether aerobic exercise exerts mood-modulating effects through an estrogen signaling mechanism. Method: The experiment was divided into two parts. The first part is to compare the three modeling methods to obtain the most obvious method of depression-like phenotype for further study in the second part. The first part of ovariectomized rats (age, 13 weeks) was tested when rats were 14 or 22 weeks old or in the sixth week after 3 weeks of chronic restraint stress. The second part was to treat the animals with the most obvious depression-like phenotype in different ways, placebo treatment or estradiol (E2) replacement therapy was administered, aerobic training, or estrogen receptor antagonist treatment. The cognitive (Barnes maze and 3-chamber social tests), anxiety-like (open-field and elevated plus maze tests) and depression-like (sucrose preference and forced swim tests) behaviors of rats in both parts were analyzed to study the effects of estrogen depletion and aerobic exercise. Results: Rats did not develop depressive symptoms immediately after ovariectomy, however, the symptoms became more pronounced with a gradual decrease in ovarian hormone levels. Compared with the placebo or control groups, the exercise and E2 groups showed improved performance in all behavioral test tasks, and the antidepressant effects of aerobic exercise were comparable to those of estrogen. Moreover, the estrogen receptor antagonist has markedly inhibited the antidepressant effects of aerobic exercise. Conclusion: Estrogen receptors may mediate the antidepressant effects of aerobic exercise. In addition, an increasingly fragile ovarian hormonal environment may underlies chronic restraint stress-induced depression.

Therapeutic non-invasive brain treatments in Alzheimer's disease: recent advances and challenges.

Alzheimer's disease (AD) is one of the major neurodegenerative diseases and the most common form of dementia. Characterized by the loss of learning, memory, problem-solving, language, and other thinking abilities, AD exerts a detrimental effect on both patients' and families' quality of life. Although there have been significant advances in understanding the mechanism underlying the pathogenesis and progression of AD, there is no cure for AD. The failure of numerous molecular targeted pharmacologic clinical trials leads to an emerging research shift toward non-invasive therapies, especially multiple targeted non-invasive treatments. In this paper, we reviewed the advances of the most widely studied non-invasive therapies, including photobiomodulation (PBM), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and exercise therapy. Firstly, we reviewed the pathological changes of AD and the challenges for AD studies. We then introduced these non-invasive therapies and discussed the factors that may affect the effects of these therapies. Additionally, we review the effects of these therapies and the possible mechanisms underlying these effects. Finally, we summarized the challenges of the non-invasive treatments in future AD studies and clinical applications. We concluded that it would be critical to understand the exact underlying mechanisms and find the optimal treatment parameters to improve the translational value of these non-invasive therapies. Moreover, the combined use of non-invasive treatments is also a promising research direction for future studies and sheds light on the future treatment or prevention of AD.

Non-invasive photobiomodulation treatment in an Alzheimer Disease-like transgenic rat model.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, causing neuronal degeneration and cognitive deficits that significantly impair independence and quality of life for those affected and their families. Though AD is a major neurodegenerative disease with vast avenues of investigation, there is no effective treatment to cure AD or slow disease progression. The present work evaluated the therapeutic effect of long-term photobiomodulation (PBM) treatment with continuous-wave low-level laser on AD and its underlying mechanism. Methods: PBM was implemented for 2 min, 3 times per week for 16 months in 2-month-old transgenic AD rats. A battery of behavioral tests was performed to measure the effect of PBM treatment on cognitive dysfunction in AD rats. The effects of PBM therapy on typical AD pathologies, including amyloid plaques, intracellular neurofibrillary tangles, neuronal loss, neuronal injury, neuronal apoptosis, and neurodegeneration, were then assessed. The underlying mechanisms were measured using immunofluorescence staining, western blotting analysis, mass spectrometry, primary cortical and hippocampal cell cultures, and related assay kits. Results: PBM treatment significantly improved the typical AD pathologies of memory loss, amyloid plaques, tau hyperphosphorylation, neuronal degeneration, spine damage, and synaptic loss. PBM treatment had several mechanistic effects which may explain these beneficial effects, including 1) regulation of glial cell polarization and inhibition of neuroinflammation, 2) preservation of mitochondrial dynamics by regulating fission and fusion proteins, and 3) suppression of oxidative damage to DNA, proteins, and lipids. Furthermore, PBM enhanced recruitment of microglia surrounding amyloid plaques by improving the expression of microglial IL-3Rα and astrocytic IL-3, which implies a potential role of PBM in improving Aß clearance. Finally, our results implicate neuronal hemoglobin in mediating the neuroprotective effect of PBM, as Hbα knockdown abolished the neuroprotective effect of PBM treatment. Conclusion: Collectively, our data supports the potential use of PBM treatment to prevent or slow the progression of AD and provides new insights into the molecular mechanisms of PBM therapy.

Long-term exercise pre-training attenuates Alzheimer's disease-related pathology in a transgenic rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. Despite enormous efforts around the world, there remains no effective cure for AD. This study was performed to investigate the effects of long-term exercise pretreatment on the typical pathology of AD in a novel transgenic AD rat model. Male 2-month-old animals were divided into the following groups: wild-type (WT) rats, AD rats, and AD rats with treadmill exercise pretreatment (AD-Exe). After exercise pretreatment, the Barnes maze task, passive avoidance task, and cued fear conditioning test were performed to test learning and memory function. The elevated plus maze, open field test, sucrose preference test, and forced swim test were conducted to measure anxious-depressive-like behavior. Immunofluorescence staining, Golgi staining, transmission electron microscopy, Western blot analysis, F-Jade C staining, TUNEL staining, and related assay kits were conducted to measure Aß plaques, tau hyperphosphorylation, neuronal damage, neuronal degeneration, dendritic spine density, synapses, synaptic vesicles, mitochondrial morphology, mitochondrial dynamic, oxidative stress, and neuroinflammation. Behavioral tests revealed that long-term exercise pretreatment significantly alleviated learning and memory dysfunction and anxious-depressive-like behaviors in AD animals. In addition, exercise pretreatment attenuated amyloid-ß deposition and tau hyperphosphorylation and preserved spine density, synapses, and presynaptic vesicles. Exercise also inhibited neuronal damage, neuronal apoptosis, and neuronal degeneration. Additional studies revealed the imbalance of mitochondrial dynamics was significantly inhibited by exercise pretreatment accompanied by a remarkable suppression of oxidative stress and neuroinflammation. Our findings suggest that long-term exercise pretreatment alleviated behavioral deficits and typical pathologies of the AD rat model, supporting long-term exercise pretreatment as a potential approach to delay the progression of AD.

Intranasal administration of DHED protects against exhaustive exercise-induced brain injury in rats.

DHED (10ß,17ß-dihydroxyestra-1,4-dien-3-one) is a brain-selective prodrug of 17ß-estradiol and has been reported to have a strong neuroprotective effect. In this study, the exhaustive swimming rat model was used to investigate the therapeutic effects and mechanisms of intranasal DHED treatment. Male eight-week-old healthy Sprague Dawley rats were randomly divided into three groups: control group (Cont), exhaustive swimming (ES), and DHED + exhaustive swimming (DHED). The open-field test and beam-walking test were performed to measure exploratory behavior and general activity in rats. Immunofluorescence staining, western blotting, ELISA analysis and related assay kits were applied to measure brain damage, inflammatory cytokines, and apoptosis pathways. Behavioral data shows that DHED intranasal administration can prevent neurobehavioral impairment caused by exhaustive swimming. Using a series of bioanalytical assays, we demonstrated that DHED markedly abated neuronal injury compared to the exhaustive swimming group, as evidenced by the reduced expression of apoptosis-regulated proteins, the improvement of neural survival, and the prevention of myelin loss. In addition, mitochondrial fission was attenuated distinctly, and a dynamic equilibrium was restored. Intranasal administration of DHED likewise significantly suppressed reactive gliosis and the release of inflammatory cytokines in the rat cerebral motor cortex. Consistent with previous reports, DHED treatment ameliorated changes of excitatory neurotransmitters. These results provide strong support for the promising therapeutic effects of DHED on neuroprotection during exhaustive swimming. The underlying mechanisms may rely on mitochondrial dynamics, neuroinflammation, and the balance of neurotransmitters.

Photobiomodulation Therapy Attenuates Anxious-Depressive-Like Behavior in the TgF344 Rat Model.

BACKGROUND: Anxious-depressive-like behavior has been recognized as an early endophenotype in Alzheimer's disease (AD). Recent studies support early treatment of anxious-depressive-like behavior as a potential target to alleviate memory loss and reduce the risk of developing dementia. We hypothesize that photobiomodulation (PBM) could be an effective method to alleviate depression and anxiety at the early stage of AD pathogenesis. OBJECTIVE: To analyze the effect of PBM treatment on anxious-depressive-like behavior at the early stage of AD. METHODS: Using a novel transgenic AD rat model, animals were divided into wild-type, AD+sham PBM, and AD+PBM groups. Two-minute daily PBM (irradiance: 25 mW/cm2 and fluence: 3 J/cm2 at the cortical level) was applied transcranially to the brain of AD animals from 2 months of age to 10 months of age. After completing PBM treatment at 10 months of age, behavioral tests were performed to measure learning, memory, and anxious-depressive-like behavior. Neuronal apoptosis, neuronal degeneration, neuronal damage, mitochondrial function, neuroinflammation, and oxidative stress were measured to test the effects of PBM on AD animals. RESULTS: Behavioral tests showed that: 1) no spatial memory deficits were detected in TgF344 rats at 10 months of age; 2) PBM alleviated anxious-depressive-like behavior in TgF344 rats; 3) PBM attenuated neuronal damage, degeneration, and apoptosis; and 4) PBM suppresses neuroinflammation and oxidative stress. CONCLUSION: Our findings support our hypothesis that PBM could be an effective method to alleviate depression and anxiety during the early stage of AD development. The mechanism underlying these beneficial effects may be due to the improvement of mitochondria function and integrity and the inhibition of neuroinflammation and oxidative stress.

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring.

Neonatal hypoxic-ischemic (HI) injury is a severe complication often leading to neonatal death and long-term neurobehavioral deficits in children. Currently, the only treatment option available for neonatal HI injury is therapeutic hypothermia. However, the necessary specialized equipment, possible adverse side effects, and limited effectiveness of this therapy creates an urgent need for the development of new HI treatment methods. Photobiomodulation (PBM) has been shown to be neuroprotective against multiple brain disorders in animal models, as well as limited human studies. However, the effects of PBM treatment on neonatal HI injury remain unclear. Methods: Two-minutes PBM (808 nm continuous wave laser, 8 mW/cm2 on neonatal brain) was applied three times weekly on the abdomen of pregnant rats from gestation day 1 (GD1) to GD21. After neonatal right common carotid artery ligation, cortex- and hippocampus-related behavioral deficits due to HI insult were measured using a battery of behavioral tests. The effects of HI insult and PBM pretreatment on infarct size; synaptic, dendritic, and white matter damage; neuronal degeneration; apoptosis; mitochondrial function; mitochondrial fragmentation; oxidative stress; and gliosis were then assessed. Results: Prenatal PBM treatment significantly improved the survival rate of neonatal rats and decreased infarct size after HI insult. Behavioral tests revealed that prenatal PBM treatment significantly alleviated cortex-related motor deficits and hippocampus-related memory and learning dysfunction. In addition, mitochondrial function and integrity were protected in HI animals treated with PBM. Additional studies revealed that prenatal PBM treatment significantly alleviated HI-induced neuroinflammation, oxidative stress, and myeloid cell/astrocyte activation. Conclusion: Prenatal PBM treatment exerts neuroprotective effects on neonatal HI rats. Underlying mechanisms for this neuroprotection may include preservation of mitochondrial function, reduction of inflammation, and decreased oxidative stress. Our findings support the possible use of PBM treatment in high-risk pregnancies to alleviate or prevent HI-induced brain injury in the perinatal period.