Current Neuropharmacology - Online First

Alzheimer's Disease (AD) is an exhausting neurodegenerative condition marked by the build-up of abnormal protein aggregates in the brain and a progressive loss of cognitive function. The complicated role that protein kinases play in the pathophysiology of AD has come to light more and more in recent years. The symptoms of AD include memory loss, cognitive impairment, and neuronal malfunction. Many cellular processes, including synaptic plasticity, neuronal survival, and protein homeostasis, have been linked to protein kinases, a class of enzymes that control phosphorylation. The etiology of AD has been closely related to the dysregulation of protein kinases, including those implicated in the phosphorylation of tau and the formation of amyloid-beta. GSK-3, also known as glycogen synthase kinase, is one of the most studied protein kinases in Alzheimer's disease. It is known that GSK-3 phosphorylates tau protein, causing it to clump together and create neurofibrillary tangles. Moreover, GSK-3 activation increases the development of amyloid-beta, which furthers the disease's progression. Additional protein kinases, including Cyclin-Dependent Kinase 5 (CDK5) and calcium/calmodulin-dependent protein kinase II (CaMKII), have also been connected to tau phosphorylation and synaptic dysfunction in AD. Protein kinases play a crucial role in the pathophysiology of AD, extending beyond tau phosphorylation. Research has shown that Amyloid Precursor Protein (APP) processing is regulated by Protein Kinases A (PKA) and C (PKC), which affects the production and clearance of amyloid-beta. Furthermore, AD etiology involves oxidative stress, neuroinflammation, and mitochondrial dysfunction, all of which are regulated by protein kinases. This study will cover the effects of protein kinases in AD, focusing on their role in tau phosphorylation, an attribute of the disease. We will also address the role of protein kinase in the development of amyloid-beta, synaptic malfunction, and neuroinflammation.

Mitochondria play a critical role in immune cell differentiation, activation, and the regulation of innate immune responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key mediator of cytosolic DNA sensing and contributes to a broad spectrum of pathological processes, including infectious diseases, sterile inflammation, cancer, and autoimmune disorders. STING is activated in response to cytosolic DNA during infection and can restrict translation in RNA virus-infected cells as part of the innate immune response. Studies have shown that mitochondrial dysfunction, particularly the release of mitochondrial DNA (mtDNA), can act as a potent trigger of cGAS-STING signaling, linking mitochondrial damage to immune activation. Additionally, this pathway intersects with autophagy, metabolic regulation, and cell death mechanisms. This comprehensive review summarizes current advances in understanding the cGAS-STING axis and mtDNA release in the context of mitochondrial dysfunction, with a focus on their roles in disease pathogenesis and potential as therapeutic targets. We highlight recent progress in the development of targeted interventions and emphasize the importance of elucidating the regulatory mechanisms underlying STING activation in various pathological conditions, including neuroinflammation, cancer, ischemia/reperfusion injury, and autoimmune diseases.

Post-traumatic stress disorder (PTSD) is a chronic and multifactorial psychiatric condition that is often underdiagnosed, particularly when associated with chronic diseases (CDs). These conditions arise from complex interactions among psychosocial, socioeconomic, epigenetic, immune, metabolic, and neurobiological factors. Current treatment options for PTSD and CDs, whether isolated or comorbid, remain suboptimal. Addressing the bidirectional relationship between PTSD and CDs is a pressing global public health challenge, necessitating a deeper understanding of the underlying molecular mechanisms. This review examines the interplay of stress-response and neurochemical factors in PTSD and CDs, highlighting how maladaptive stress responses to trauma can disrupt neurochemical pathways, contributing to the development of CDs, and vice versa. Despite this, a significant gap exists in the number of in vivo model studies that adequately mimic the comorbid symptoms of PTSD and CDs, hindering progress in elucidating shared cellular and molecular pathways. This limitation restricts therapeutic advancements. Therefore, a comprehensive understanding of the neurobiological dysfunctions in the brain and their crosstalk with the immune, cardiovascular, and endocrine systems is critical. Such insights will pave the way for individualized treatment strategies tailored to the unique profiles of patients with PTSD associated with CDs.

Ageing is a complex biological process marked by a gradual decline in bodily functions at the cellular, tissue, and organ levels, resulting from molecular damage and environmental influences. It increases disease risk, particularly in older adults with neurodegenerative conditions characterized by progressive neuronal loss and neurological symptoms such as cognitive and motor impairments. Key mechanisms include abnormal protein accumulation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. Disruption of cellular homeostasis prevents the maintenance of internal conditions such as pH and glucose levels. Mitochondria, known as the cell’s “powerhouses,” are essential for ATP production, DNA protection, and metabolic regulation, supporting cellular structures. Their dysfunction plays a crucial role in the progression of neurodegenerative diseases. Factors like chronic inflammation, ATP deficiency, excessive production of reactive oxygen species (ROS), and calcium imbalance leads to oxidative stress and neuronal damage, exacerbating neurodegeneration. Current therapies mainly focus on symptom relief, emphasizing the urgent need for new treatment strategies. Given the key role of mitochondrial dysfunction, therapies aiming to restore mitochondrial homeostasis are gaining increasing attention. Mitochondrial antioxidants such as MitoQ, MitoTEMPO, and SkQ1 have shown neuroprotective, anti-inflammatory, and antioxidant properties. Research into their therapeutic potential may lead to the development of effective drugs that restore mitochondrial function and improve quality of life of the patients.

Neurological and psychiatric diseases pose a considerable global burden. Exploring additional potential prevention strategies and therapies is ongoing. As a prevalent natural product and nutraceutical from food, betaine’s pharmaceutical applications suggest benefits for both health and disease in multiple organs. Recently, its efficacy on neurological and psychiatric health has been proposed and has drawn considerable attention. This review aims to provide an updated, critical, and comprehensive profile of the promising medicinal roles of betaine in these diseases. In addition to its well-known osmotic protection, due to methyl donation, it regulates metabolism, alleviates oxidative stress, and reduces inflammation. To manifest neurological and psychiatric health benefits, betaine acts by affecting gamma-aminobutyric acid associated with its transporters, related neurotransmitters, downstream and neurological pathways, and other specific mechanisms in the nervous system. Betaine demonstrates therapeutic potential against various neurological and psychiatric diseases, such as epilepsy, neurocognitive disorders (including Alzheimer's disease), Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury, depression, anxiety, schizophrenia, autism spectrum disorder, sleep disorders, fetal alcohol syndrome, syringomyelia, neonatal brain injury, neuropathic pain, and motor dysfunction. Despite the promising role of betaine in the treatment, diagnosis, and prevention of neuropsychiatric disorders, much of the present evidence appears to be fragmentary. Further studies elucidating the underlying mechanisms and direct clinical applications are required to obtain a deeper understanding of betaine and its underutilized potential. Overall, this review highlights the potential of betaine as a promising agent with benefits for neurological and psychiatric diseases, aiming to offer clues to advance this field.

Multiple Sclerosis (MS), the most common demyelinating disease of the Central Nervous System (CNS), is characterized in its pathogenesis by an interplay of mechanisms pertaining to aberrant immune response, acute and chronic inflammation, glial housekeeping, and neuron survival, ultimately resulting in demyelination, synaptic dysfunction, and neuroaxonal loss. Experimental models as well as epidemiological observations support the hypothesis of a role of diet in the disease onset, activity, and progression. It has been suggested that Western-type diets might be detrimental, while on the other hand, certain dietary regimens, like Mediterranean, low-fat, ketogenic, or intermittent fasting, might lead to disease amelioration, possibly through differential regulatory effects upon inflammation, immunity, and regenerative processes of neurons and glia. Under this perspective, immunometabolites, small intermediates including among the others citrate, itaconate, lactate, glutamate, glutamine, alfa-ketoglutarate, 2-hydroxyglutarate, fumarate, ceramides, whose turn-over reflects metabolic reprogramming of immune cells, might be viewed as significant regulators of cellular responses against either local or systemic noxious stimuli, both in the periphery and in the CNS. The present narrative review aims at summarizing current experimental and clinical evidence regarding the role of immunometabolites in shaping MS pathology, to address whether they could be relevant either as disease markers or therapeutic targets, and whether they might be differentially influenced by dietary approaches, especially by Mediterranean Pattern Diets (MPD).

Neurological disorders are marked by neurodegeneration, leading to impaired cognition, psychosis, and mood alterations. These symptoms are typically associated with functional changes in both emotional and cognitive processes, which are often correlated with anatomical variations in the brain. Hence, brain structural magnetic resonance imaging (MRI) data have become a critical focus in research, particularly for predictive modeling. The involvement of large MRI data consortia, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), has facilitated numerous MRI-based classification studies utilizing advanced artificial intelligence models. Among these, convolutional neural networks (CNNs) and non-convolutional artificial neural networks (NC-ANNs) have been prominently employed for brain image processing tasks. These deep learning models have shown significant promise in enhancing the predictive performance for the diagnosis of neurological disorders, with a particular emphasis on Alzheimer's disease (AD). This review aimed to provide a comprehensive summary of these deep learning studies, critically evaluating their methodologies and outcomes. By categorizing the studies into various sub-fields, we aimed to highlight the strengths and limitations of using MRI-based deep learning approaches for diagnosing brain disorders. Furthermore, we discussed the potential implications of these advancements in clinical practice, considering the challenges and future directions for improving diagnostic accuracy and patient outcomes. Through this detailed analysis, we seek to contribute to the ongoing efforts in harnessing AI for better understanding and management of AD.