Neuroscience Insights最新文献

The transient receptor potential (TRP) superfamily of ion channels in humans comprises voltage-gated, non-selective cation channels expressed both in excitable as well as non-excitable cells. Four TRP channel subunits associate to create functional homo- or heterotetramers that allow the influx of calcium, sodium, and/or potassium. These channels are highly abundant in the brain and kidney and are important mediators of diverse biological functions including thermosensation, vascular tone, flow sensing in the kidney and irritant stimuli sensing. Inherited or acquired dysfunction of TRP channels influences cellular functions and signaling pathways resulting in multifaceted disorders affecting skeletal, renal, cardiovascular, and nervous systems. Studies have demonstrated the involvement of these channels in the generation and transduction of pain. Based on the multifaceted role orchestrated by these TRP channels, modulation of the activity of these channels presents an important strategy to influence cellular function by regulating intracellular calcium levels as well as membrane excitability. Therefore, there has been a remarkable pharmaceutical inclination toward TRP channels as therapeutic interventions. Several candidate drugs influencing the activity of these channels are already in the clinical trials pipeline. The present review encompasses the current understanding of TRP channels and TRP modulators in pain and pain management.

Previous research has documented elevated risk of brain cancer in patients with multiple sclerosis (MS). Separately, human leukocyte antigen (HLA) has been implicated in protection or susceptibility for both conditions. The aim of the current study was to assess a possible role of shared immunogenetic influence on risk of MS and brain cancer. We first identified an immunogenetic profile for each condition based on the covariance between the population frequency of 127 high-resolution HLA alleles and the population prevalence of each condition in 14 Continental Western European countries and then evaluated the correspondence between MS and brain cancer immunogenetic profiles. Also, since each individual carries 12 HLA alleles (2 × 6 genes), we estimated HLA protection and susceptibility for MS and brain cancer at the individual level. We found that the immunogenetic profiles of MS and brain cancer were highly correlated overall (P < .001) and across all 6 HLA genes with the strongest association observed for DRB1, followed by DQB1 and HLA-A. These findings of immunogenetic overlap between MS and brain cancer are discussed in light of the role of HLA in the immune system response to viruses and other foreign antigens.

Studying proteomics data of the human brain could offer numerous insights into unraveling the signature of resilience to Alzheimer's disease. In our previous study with rigorous cohort selection criteria that excluded 4 common comorbidities, we harnessed multiple brain regions from 43 research participants with 12 of them displaying cognitive resilience to Alzheimer's disease. Based on the previous findings, this work focuses on 6 proteins out of the 33 differentially expressed proteins associated with resilience to Alzheimer's disease. These proteins are used to construct a decision tree classifier, enabling the differentiation of 3 groups: (i) healthy control, (ii) resilience to Alzheimer's disease, and (iii) Alzheimer's disease with dementia. Our analysis unveiled 2 important regional proteomic markers: Aβ peptides in the hippocampus and PA1B3 in the inferior parietal lobule. These findings underscore the potential of using distinct regional proteomic markers as signatures in characterizing the resilience to Alzheimer's disease.

Initially, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-2019 (COVID-19), was predominantly considered to primarily affect the respiratory system. However, later studies revealed that it also affects brain function through its ability to bind to the angiotensin-converting enzyme type 2 (ACE2) receptors expressed on neural cells. Our study involved a comprehensive review of literature aiming to investigate the relationship between COVID-19 and the development of depression. Our analysis shows a connection between these 2 conditions, as a consequence of the inflammatory response in the nervous system to the COVID-19 virus and the psychophysiological effects of the pandemic. In COVID-19 patients, depression can arise either due to the direct viral infection of the brain or as a result of an indirect immune response triggering neuroinflammation after a cytokine storm. The resulting depression can be treated with non-pharmacological therapies such as psychotherapy, antidepressant medications, or a combination of these treatments depending on the severity of the symptoms.

The SARS-CoV-2 virus caused an unprecedented pandemic around the globe, infecting 36.5 million people and causing the death of over 1 million in the United States of America alone. COVID-19 patients demonstrated respiratory symptoms, cardiovascular complications, and neurologic symptoms, which in most severe cases included encephalopathy and encephalitis. Hypoxia and the uncontrolled proliferation of cytokines are commonly recognized to cause encephalopathy, while the retrograde trans-synaptic spread of the virus is thought to cause encephalitis in SARS-CoV-2-induced pathogenesis. Although recent research revealed some mechanisms explaining the development of neurologic symptoms, it still remains unclear whether interactions between these mechanisms exist. This review focuses on the discussion and analysis of previously reported hypotheses of SARS-CoV-2-induced encephalopathy and encephalitis and looks into possible overlaps between the pathogenesis of both neurological outcomes of the disease. Promising therapeutic approaches to prevent and treat SARS-CoV-2-induced neurological complications are also covered. More studies are needed to further investigate the dominant mechanism of pathogenesis for developing more effective preventative measures in COVID-19 cases with the neurologic presentation.

The urgent need for medical treatments of alcohol use disorders has motivated the search for novel molecular targets of alcohol response. Most studies exploit the strengths of lab animals without considering how these and other species may have adapted to respond to alcohol in an ecological context. Here, we provide an evolutionary perspective on the molecular and genetic underpinnings of alcohol consumption by reviewing evidence that alcohol metabolic enzymes have undergone adaptive evolution at 2 evolutionary junctures: first, to enable alcohol consumption accompanying the advent of a frugivorous diet in a primate ancestor, and second, to decrease the likelihood of excessive alcohol consumption concurrent with the spread of agriculture and fermentation in East Asia. By similarly considering how diverse vertebrate and invertebrate species have undergone natural selection for alcohol responses, novel conserved molecular targets of alcohol are likely be discovered that may represent promising therapeutic targets.

Several studies have shown that amyloid-β (Aβ) deposition below the clinically relevant cut-off levels is associated with subtle changes in cognitive function and increases the risk of developing future Alzheimer's disease (AD). Although functional MRI is sensitive to early alterations occurring during AD, sub-threshold changes in Aβ levels have not been linked to functional connectivity measures. This study aimed to apply directed functional connectivity to identify early changes in network function in cognitively unimpaired participants who, at baseline, exhibit Aβ accumulation below the clinically relevant threshold. To this end, we analyzed baseline functional MRI data from 113 cognitively unimpaired participants of the Alzheimer's Disease Neuroimaging Initiative cohort who underwent at least one ¹⁸F-florbetapir-PET after the baseline scan. Using the longitudinal PET data, we classified these participants as Aβ negative (Aβ-) non-accumulators (n = 46) and Aβ- accumulators (n = 31). We also included 36 individuals who were amyloid-positive (Aβ+) at baseline and continued to accumulate Aβ (Aβ+ accumulators). For each participant, we calculated whole-brain directed functional connectivity networks using our own anti-symmetric correlation method and evaluated their global and nodal properties using measures of network segregation (clustering coefficient) and integration (global efficiency). When compared to Aβ- non-accumulators, the Aβ- accumulators showed lower global clustering coefficient. Moreover, the Aβ+ accumulator group exhibited reduced global efficiency and clustering coefficient, which at the nodal level mainly affected the superior frontal gyrus, anterior cingulate cortex, and caudate nucleus. In Aβ- accumulators, global measures were associated with lower baseline regional PET uptake values, as well as higher scores on the Modified Preclinical Alzheimer Cognitive Composite. Our findings indicate that directed connectivity network properties are sensitive to subtle changes occurring in individuals who have not yet reached the threshold for Aβ positivity, which makes them a potentially viable marker to detect negative downstream effects of very early Aβ pathology.

The term mild cognitive impairment (MCI) defines an intermediate state between normal aging and dementia. Vascular cognitive impairment refers to a decline in cognitive function that is caused by or associated with vascular disease and comprises all the spectrum of cognitive impairments, from MCI of vascular origin to vascular dementia. One of the available treatments for cognitive impairment is cytidine diphosphate-choline (CDP-Choline), or citicoline. The objective of the present manuscript is to provide complete evidence about the efficacy of citicoline for MCI, especially of vascular origin, but also due to other neurodegenerative disorders. Citicoline is a pharmaceutical product constituted by the combination of 2 natural molecules (cytidine and choline) and is marketed as a food supplement. It has been proposed to provide neuroprotective effects through diverse mechanisms of action. Taking into account the available literature, citicoline has shown a consistent improvement in cognitive function in patients with MCI, especially of vascular origin. Moreover, it provides beneficial effects on vascular, Alzheimer, and mixed dementias, stroke sequelae, intracerebral hemorrhages, traumatic brain injuries, and neurodegenerative diseases. Long-term treatment with citicoline has also been demonstrated to be well-tolerated and has not been associated with severe adverse events. Citicoline is a safe, well-tolerated, and promising agent with evidenced neuroprotective properties.

Neural progenitor cell (NPC) transplantation is a promising potential therapy for replacing spinal cord neurons and glial cells following spinal cord injury (SCI). Despite the rapid advancement of NPC transplantation to SCI clinical trials, we still lack understanding of fundamental biology underlying how NPC grafts interact with the injured host nervous system. Our recent study demonstrated a potent effect of biological sex mismatch between donor and host on graft immune rejection. Here we discuss the implications of this study in the context of clinical trials for SCI, and important topics for future research in SCI cell transplantation.