Current Neuropharmacology - Online First

Neurodegenerative diseases (NDDs) are a multifaceted and heterogeneous group of complex diseases. Unfortunately, a cure for these conditions has yet to be found, but there are ways to reduce the risk of developing them. Studies have shown that specific vitamins regulate the brain molecules and signaling pathways, which may help prevent degeneration. This review focuses on examining the role of vitamins in preventing five significant types of neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). This review also highlights promising and controversial findings about the potential impact of vitamins on this group of diseases. Several developed countries standardize daily dietary vitamin intake to meet nutrient requirements, improve health, and prevent chronic diseases like NDDs. However, more research is necessary to gain a more comprehensive understanding of their therapeutic benefits, including studies exploring different drug-dose paradigms, diverse humanized animal models, and clinical trials conducted in various

COVID-19 is associated with neuropsychiatric symptoms, such as anosmia, anxiety, depression, stress-related reactions, and psychoses. The illness can cause persistent cognitive impairment and “brain fog”, suggesting chronic brain involvement. Clinical entities of ongoing symptomatic COVID-19 and Post COVID Syndrome (PCS) mainly present neuropsychiatric symptoms such as dysgeusia, headache, fatigue, anxiety, depression, sleep disturbances, and post-traumatic stress disorder. The pathophysiology of COVID-19-related brain damage is unclear, but it is linked to various mechanisms such as inflammation, oxidative stress, immune dysregulation, impaired glutamate homeostasis, glial and glymphatic damage, and hippocampal degeneration. Noteworthy is that the metabotropic receptor mGluR2 was discovered as a mechanism of internalisation of SARS-CoV-2 in Central Nervous System (CNS) cells. N-acetylcysteine (NAC) and acetyl-L-carnitine (ALC) are two supplements that have already been found effective in treating psychiatric conditions. Furthermore, NAC showed evidence in relieving cognitive symptomatology in PCS, and ALC was found effective in treating depressive symptomatology of PCS. The overlapping effects on the glutamatergic system of ALC and NAC could help treat COVID-19 psychiatric symptoms and PCS, acting through different mechanisms on the xc-mGluR2 network, with potentially synergistic effects on chronic pain and neuro-astrocyte protection. This paper aims to summarise the current evidence on the potential therapeutic role of NAC and ALC, providing an overview of the underlying molecular mechanisms and pathophysiology. It proposes a pathophysiological model explaining the effectiveness of NAC and ALC in treating COVID-19-related neuropsychiatric symptoms.

Sepsis-associated encephalopathy (SAE) is a form of cognitive and psychological impairment resulting from sepsis, which occurs without any central nervous system infection or structural brain injury. Patients may experience long-term cognitive deficits and psychiatric disorders even after discharge. However, the underlying mechanism remains unclear. As cognitive function and mental disease are closely related to synaptic plasticity, it is presumed that alterations in synaptic plasticity play an essential role in the pathological process of SAE. Here, we present a systematic description of the pathogenesis of SAE, which is primarily driven by glial cell activation and subsequent release of inflammatory mediators. Additionally, we elucidate the alterations in synaptic plasticity that occur during SAE and comprehensively discuss the roles played by glial cells and inflammatory factors in this process. In this review, we mainly discuss the synaptic plasticity of SAE, and the main aim is to show the consequences of SAE on inflammatory factors and how they affect synaptic plasticity. This review may enhance our understanding of the mechanism underlying cognitive dysfunction and provide valuable insights into identifying appropriate therapeutic targets for SAE.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly, and the mechanisms of AD have not been fully defined. Circular RNAs (circRNAs), covalently closed RNAs produced by reverse splicing, have critical effects in the pathogenesis of AD. CircRNAs participate in production and clearance of Aβ and tau, regulate neuroinflammation, synaptic plasticity and the process of apoptosis and autophagy, indicating that circRNAs may be alternative biomarkers and therapeutic targets. Our review summarizes the functions of circRNAs in the progression and development of AD, which provide insights into the prospect of circRNAs in the diagnosis and treatment of AD.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4-hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.