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.

Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain.

Serum/Glucocorticoid Regulated Kinase 1 (SGK1), a serine/threonine kinase, is ubiquitous across a wide range of tissues, orchestrating numerous signaling pathways and associated with various human diseases. SGK1 has been extensively explored in diverse types of immune and inflammatory diseases, cardiovascular disorders, as well as cancer metastasis. These studies link SGK1 to cellular proliferation, survival, metabolism, membrane transport, and drug resistance. Recently, increasing research has focused on SGK1's role in neurological disorders, including a variety of neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease and Parkinson's disease), brain injuries (e.g., cerebral ischemia and traumatic brain injury), psychiatric conditions (e.g., depression and drug addiction). SGK1 is emerging as an increasingly compelling therapeutic target across the spectrum of neurological disorders, supported by the availability of several effective agents. However, the conclusions of many studies observing the prevalence and function of SGK1 in neurological disorders are contradictory, necessitating a review of the SGK1 research within neurological disorders. Herein, we review recent literature on SGK1's primary functions within the nervous system and its impacts within different neurological disorders. We summarize significant findings, identify research gaps, and outline possible future research directions based on the current understanding of SGK1 to help further progress the understanding and treatment of neurological disorders.

The role of serum/glucocorticoid-regulated kinase 1 in brain function following cerebral ischemia.

Cardiopulmonary arrest (CA) is a major cause of death/disability in the U.S. with poor prognosis and survival rates. Current therapeutic challenges are physiologically complex because they involve hypoperfusion (decreased cerebral blood flow), neuroinflammation, and mitochondrial dysfunction. We previously discovered novel serum/glucocorticoid-regulated kinase 1 (SGK1) is highly expressed in brain of neurons that are susceptible to ischemia (hippocampus and cortex). We inhibited SGK1 and utilized pharmacological (specific inhibitor, GSK650394) and neuron-specific genetic approaches (shRNA) in rodent models of CA to determine if SGK1 is responsible for hypoperfusion, neuroinflammation, mitochondrial dysfunctional, and neurological deficits after CA. Inhibition of SGK1 alleviated cortical hypoperfusion and neuroinflammation (via Iba1, GFAP, and cytokine array). Treatment with GSK650394 enhanced mitochondrial function (via Seahorse respirometry) in the hippocampus 3 and 7 days after CA. Neuronal injury (via MAP2, dMBP, and Golgi staining) in the hippocampus and cortex was observed 7 days after CA but ameliorated with SGK1-shRNA. Moreover, SGK1 mediated neuronal injury by regulating the Ndrg1-SOX10 axis. Finally, animals subjected to CA exhibited learning/memory, motor, and anxiety deficits after CA, whereas SGK1 inhibition via SGK1-shRNA improved neurocognitive function. The present study suggests the fundamental roles of SGK1 in brain circulation and neuronal survival/death in cerebral ischemia-related diseases.

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.

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.

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.