Molecular Neurobiology

Acetyl-l-carnitine (ALC), the acetyl ester of l-carnitine, is a naturally occurring substance that when administered at supraphysiological concentrations is neuroprotective. ALC plays an essential role in intermediary and mitochondrial metabolism. It has also neurotrophic and antioxidant actions. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various etiologies, and it is a molecule of considerable interest for its clinical application in various neural disorders, such as Alzheimer’s disease and painful neuropathies, although little is known regarding the effects of ALC on gene expression. Suppression subtractive hybridization methodology was used for the generation of subtracted complementary DNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after a chronic ALC treatment. In the present paper, we provide evidences for the up-regulation of the expression of prostaglandin D2 synthase, brain-specific Na+-dependent inorganic phosphate transporter, and cytochrome b oxidase, bc1 complex induced in the rat brain by ALC. On the contrary, ALC treatment down-regulates the expression of the gene of ferritin-H. Altogether, these results suggest that ALC might play a cytoprotective role against various brain stressors.

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1β in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.

Excessive inflammation is a major cause contributing to early brain injury (EBI) and is associated with negative or catastrophic outcomes of subarachnoid hemorrhage (SAH). Resolvin D1 (RvD1) exerts strong anti-inflammatory and pro-resolving effects on either acute or chronic inflammation of various origin. Henceforth, we hypothesized that RvD1 potentially attenuates excessive inflammation in EBI following SAH. Therefore, we generated a filament perforation SAH model and administered 3 different doses (0.3, 0.6, and 1.2 nmol) of RvD1 after experimental SAH. Neurological scores, brain edema, and blood–brain barrier integrity were evaluated; besides, neutrophil infiltration, neuronal deaths, and microglial pro-inflammatory polarization were observed using histopathology or immunofluorescence staining, western blots, and qPCR. After confirming the effectiveness of RvD1 in SAH, we administered the FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4) 30 min before SAH establishment to observe whether this compound could abolish the anti-inflammatory effect of RvD1. Altogether, our results showed that RvD1 exerted a strong anti-inflammatory effect and markedly reduced neutrophil infiltration and microglial pro-inflammatory activation, leading to remarkable improvements in neurological function and brain tissue restoration. After addition of WRW4, the anti-inflammatory effects of RvD1 were abolished. These results indicated that RvD1 could exert a good anti-inflammatory effect and alleviate EBI, which suggested that RvD1 might be a novel therapeutic alternative for SAH-induced injury.

The PICALM rs541458 T allele has been recognized as a risk factor for late-onset Alzheimer’s disease, and age might modulate the effects that genetic factors have on cognitive functions and brain. Thus, the current study intended to examine whether the effects of rs541458 on cognitive functions, brain structure, and function were modulated by age in non-demented Chinese elderly. We enrolled 638 subjects aged 50 to 82 years and evaluated their cognitive functions through a series of neuropsychological tests. Seventy-eight of these participants also received T1-weighted structural and resting state functional magnetic resonance imaging. Dividing subjects into groups <65 and ≥65 years old, results of neuropsychological tests showed that interactive effects of rs541458 × age existed with regard to executive function and processing speed after controlling for gender, years of education and APOE ε4 status. In addition, the effects of rs541458 on resting state functional connectivity of left superior parietal gyrus within left frontal-parietal network and on gray matter volume of left middle temporal gyrus were modulated by age. Furthermore, reduction of functional connectivity of left superior parietal gyrus was closely related with better executive function in the T allele carriers <65 years old. Further, greater volume of left middle temporal gyrus was significantly related to better executive function in both CC genotype <65 years old and CC genotype ≥65 years old groups, separately. Pending further confirmation from additional studies, our results support the hypothesis that the modulation of age, with respect to the rs541458, has interactional effects on cognitive performance, brain function, and structural measurements.

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such asN-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regeneration may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

The majority of Alzheimer’s disease (AD) cases are sporadic with unknown causes. Many dietary factors including excessive alcohol intake have been reported to increase the risk to develop AD. The effect of alcohol on cognitive functions and AD pathogenesis remains elusive. In this study, we investigated the relationship between ethanol exposure and Alzheimer’s disease. Cell cultures were treated with ethanol at different dosages for different durations up to 48 h and an AD model mouse was fed with ethanol for 4 weeks. We found that ethanol treatment altered amyloid β precursor protein (APP) processing in cells and transgenic AD model mice. High ethanol exposure increased the levels of APP and beta-site APP cleaving enzyme 1 (BACE1) and significantly promoted amyloid β protein (Aβ) production both in vitro and in vivo. The upregulated APP and BACE1 expressions upon ethanol treatment were at least partially due to the activation of APP and BACE1 transcriptions. Furthermore, ethanol treatment increased the deposition of Aβ and neuritic plaque formation in the brains and exuberated learning and memory impairments in transgenic AD model mice. Taken together, our results demonstrate that excessive ethanol intake facilitates AD pathogenesis.

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has resulted in devastating medical and economic consequences worldwide over the past 3 years. As the pandemic enters a new stage, it is essential to consider the potential impact on rare diseases such as Guillain–Barre syndrome (GBS), which has been intimately associated with COVID-19 since the first COVID-19-related GBS case was reported in January 2020. There are notable differences between COVID-19-related GBS and GBS without COVID-19 in terms of diagnostic types and clinical manifestations. Furthermore, with the widespread administration of COVID-19 vaccines, there have been reports of GBS occurring shortly after vaccination, which requires close attention despite its rarity. This review also explores the vaccines associated with heightened GBS risks, offering insights that may guide vaccination policies and clinical practice. To provide a visual summary of these findings, we have included a graphical abstract. This article will discuss the characteristic manifestations of GBS patients after being positive for the novel coronavirus and the safety of several COVID-19 vaccines. Firstly, this article comprehensively expounds and discusses the epidemiological aspects of novel coronavirus–related GBS. For example, from the perspective of the same population, the expected incidence of GBS in the COVID-19-positive population (persons/100,000 persons/ year) is about 43 times that of the COVID-19-negative population, and the incidence of GBS is significantly increased. Secondly, the clinical characteristics of COVID-19-negative GBS patients and SARS-CoV-2-GBS (SC2-GBS) patients were summarized and compared. Thirdly, this article reviews GBS cases in the current adverse events after COVID-19 vaccination and analyzes and discusses from multiple perspectives, such as the incidence of GBS events, the age proportion of patients, and the interval of onset

Vimentin is an intermediate filament (also known as nanofilament) protein expressed in several cell types of the central nervous system, including astrocytes and neural stem/progenitor cells. Mutation of the vimentin serine sites that are phosphorylated during mitosis (VIM SA/SA ) leads to cytokinetic failures in fibroblasts and lens epithelial cells, resulting in chromosomal instability and increased expression of cell senescence markers. In this study, we investigated morphology, proliferative capacity, and motility of VIM SA/SA astrocytes, and their effect on the differentiation of neural stem/progenitor cells. VIM SA/SA astrocytes expressed less vimentin and more GFAP but showed a well-developed intermediate filament network, exhibited normal cell morphology, proliferation, and motility in an in vitro wound closing assay. Interestingly, we found a two- to fourfold increased neuronal differentiation of VIM SA/SA neurosphere cells, both in a standard 2D and in Bioactive3D cell culture systems, and determined that this effect was neurosphere cell autonomous and not dependent on cocultured astrocytes. Using BrdU in vivo labeling to assess neural stem/progenitor cell proliferation and differentiation in the hippocampus of adult mice, one of the two major adult neurogenic regions, we found a modest increase (by 8%) in the fraction of newly born and surviving neurons. Thus, mutation of the serine sites phosphorylated in vimentin during mitosis alters intermediate filament protein expression but has no effect on astrocyte morphology or proliferation, and leads to increased neuronal differentiation of neural progenitor cells.

Activated microglia and their mediated inflammatory responses play an important role in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Therefore, regulating microglia activation is considered a potential therapeutic strategy. The neuroprotective effects of gastrodin were evaluated in HIBD model mice, and in oxygen glucose deprivation (OGD)-treated and lipopolysaccharide (LPS)activated BV-2 microglia cells. The potential molecular mechanism was investigated using western blotting, immunofluorescence labeling, quantitative realtime reverse transcriptase polymerase chain reaction, and flow cytometry. Herein, we found that PI3K/AKT signaling can regulate Sirt3 in activated microglia, but not reciprocally. And gastrodin exerts anti-inflammatory and antiapoptotic effects through the PI3K/AKT-Sirt3 signaling pathway. In addition, gastrodin could promote FOXO3a phosphorylation, and inhibit ROS production in LPSactivated BV-2 microglia. Moreover, the level P-FOXO3a decreased significantly in Sirt3-siRNA group. However, there was no significant change after gastrodin and siRNA combination treatment. Notably, gastrodin might also affect the production of ROS in activated microglia by regulating the level of P-FOXO3a via Sirt3. Together, this study highlighted the neuroprotective role of PI3K/AKT-Sirt3 axis in HIBD, and the anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects of gastrodin on HIBD.