Acta neurobiologiae experimentalis最新文献

APOE‑ε4 genotype (apolipoprotein E, epsilon 4) is the strongest genetic risk factor for Alzheimer's disease (AD). Despite years of research, it is still not known how it contributes to dementia development. APOE has been implicated in many AD pathology mechanisms, like Aβ clearance, brain metabolism, changes within microglia and other glial functions and inflammatory processes. In fact, immunological/inflammatory processes are recently discussed as an important factor in Alzheimer's development and granulocyte profiles changes are reported in patients. However, the exact link between the immune system and risk‑genes is unknown. In particular, it is not known whether and how they interact throughout the lifetime, before the disease onset. The aim of the study was to investigate the relationship between granulocyte count and the APOE/PICALM genes in healthy individuals with an increased genetic risk of AD. An exploratory analysis regarding other blood cells was also conducted. Blood samples were collected from 77 healthy middle‑aged (50-63 years old) participants, who were also asked to complete a health and life‑style questionnaires. Groups with different AD risk‑genes were compared. Differences in granulocyte profiles were found in healthy carriers of AD risk‑genes who had slightly elevated eosinophil levels as compared to non-risk carriers. An exploratory analysis showed some alteration in mean corpuscular hemoglobin content and concentration (MCH/MCHC) levels between risk‑carriers subgroups and non-risk carriers. No other differences in blood count or lipoprotein profile were found between healthy APOE/PICALM risk‑carriers and non-risk carriers. Longitudinal studies will reveal if and how those changes contribute to the development of AD pathology.

Coronavirus disease 2019 (COVID‑19) is an unprecedented global health concern that was declared a pandemic in March 2020. Although primarily recognized by respiratory symptoms, growing evidence suggested the causal relationship between the infection with the disease agent, namely severe acute respiratory coronavirus 2 (SARS‑CoV‑2), and neurological manifestations. Given that the virus‑induced neurological involvement is associated with a poorer prognosis, persistent neurological sequelae, and a more severe form of the disease, efforts have been made to introduce a biomarker to recognize neurological abnormalities early in the course of the disease. Studies indicate a significantly higher concentration of neurofilament light chain (NFL) in cerebrospinal fluid or blood of COVID‑19 patients versus adjusted controls. It has also been reported that COVID‑19 patients suffering from the severe form of the disease had higher NFL levels than patients with mild to moderate forms. Moreover, elevated NFL levels at hospital admission in patients who did not present primarily with neurological expressions could predict the emergence of neurological symptoms during the hospital stay. The early recognition of neurological abnormalities using the NFL biomarker could lead to escalated medical care limiting the progression of SARS‑CoV‑2‑induced central nervous system pathogenesis, resulting in a significant amelioration in disease outcome. Nevertheless, NFL assessment integrated with the evaluation of other neurodegenerative biomarkers and factors indicating disease prognosis could provide a more comprehensive estimate of disease prognosis and the extent of neurological involvement.

The Rho kinase inhibitor fasudil exerts neuroprotective effects. We previously showed that fasudil can regulate M1/M2 microglia polarization and inhibit neuroinflammation. Here, the therapeutic effect of fasudil on cerebral ischemia‑reperfusion (I/R) injury was investigated using the middle cerebral artery occlusion and reperfusion (MCAO/R) model in Sprague‑Dawley rats. The effect of fasudil on the phenotype of microglia and neurotrophic factors in the I/R brain and its potential molecular mechanism was also explored. It was found that fasudil ameliorated neurological deficits, neuronal apoptosis, and inflammatory response in rats with cerebral I/R injury. Fasudil also promoted the polarization of microglia into the M2 phenotype, in turn promoting the secretion of neurotrophic factors. Furthermore, fasudil significantly inhibited the expression of TLR4 and NF‑κB. These findings suggest that fasudil could inhibit the neuroinflammatory response and reduce brain injury after I/R injury by regulating the shift of microglia from an inflammatory M1 phenotype to an anti‑inflammatory M2 phenotype, which may be related to the regulation of the TLR4/ NF‑κB signal pathway.

Postoperative cognitive dysfunction is a postoperative complication of the central nervous system that reduces quality of life and increases mortality in perioperative patients, especially among elderly patients. Many studies have shown that the incidence of postoperative cognitive impairment in adults induced by one‑time anesthesia and surgery is very low, while multiple experiences of anesthesia and surgery can induce cognitive impairment in the developing brain. However, the effect of multiple experiences of anesthesia and surgery on cognitive function over a short period in middle‑aged mice, i.e., 6 to 8 months old, remains unclear. In this study, we explored whether the cognitive function of mice aged 6-8 months is impaired after multiple operations. Middle‑aged mice (6 to 8 months old) healthy male C57BL/6 mice underwent exploratory laparotomy under isoflurane anesthesia. Morris water maze testing was performed after the operations. Blood and brain samples were collected at 6 h, 24 h, and 48 h after the operations. Serum IL‑6, IL‑1, and S‑100β concentrations were detected by ELISA. The expressions of ChAT, AChE, and Aβ in the hippocampus were measured by western blot. Up‑regulation of Iba1 and GFAP, respectively, indicated activation of microglia and astrocytes in the hippocampus. Expression of Iba1 and GFAP was examined by immunofluorescence. The present results revealed that serum IL‑6, IL‑1β, and S‑100β concentrations were enhanced after multiple instances of anesthesia and surgery, and microglia and astrocytes in the hippocampus were activated. However, learning and memory were not impaired in the middle‑aged mice by multiple experiences of anesthesia and surgery. There were no changes in ChAT, AChE, and Aβ in the hippocampus after multiple experiences of anesthesia/surgery. Taken together, we suggest that although multiple anesthesia/surgery procedures can induce peripheral inflammation, neuroinflammation, and transient cerebral injury, it is insufficient to impair learning and memory in middle‑aged mice.

The effect of nicotine on both anxiety and depression has been broadly studied. Moreover, citalopram and citicoline play a role in the modulation of anxiety and depression. This study was designed to examine the effects of nicotine on the antidepressant and anxiolytic responses induced by citalopram and citicoline in mice. Anxiety‑ and depression‑related behaviors were assessed with the elevated plus maze and forced swim test, respectively. The results showed that subcutaneous administration of nicotine decreased open‑arm time (OAT) and open‑arm entries (OAE) but increased immobility time, suggesting anxiogenic‑like and depressive‑like effects. Intraperitoneal administration of citalopram increased OAT but decreased immobility time, indicating that citalopram induced anxiolytic‑like and antidepressant‑like responses. Additionally, an injection of citicoline increased OAE but decreased immobility time, revealing anxiolytic‑like and antidepressant‑like effects. Interestingly, the subthreshold dose of nicotine potentiated the citalopram and citicoline effects on OAT and immobility time, which revealed anxiolytic‑like and antidepressant‑like behaviors. Locomotor activity was not significantly changed by any doses of the drugs. In conclusion, these findings suggest that interactions between nicotine and citalopram or citicoline occur upon induction of anxiolytic and antidepressant responses in mice.

Autism spectrum disorders are complex behavioral disorders that can be caused by exposure to valproic acid (VPA) during pregnancy. A therapeutic role for exercise training has been reported in many neurological diseases and problems, including autism. We aimed to evaluate various intensities of endurance exercise training and investigate its effects on oxidative and antioxidant factors in the liver of young males in a rat model of autism. Female rats were divided into a treatment (autism) and a control group. The autism group received VPA intraperitoneally on day 12.5 of pregnancy and the control pregnant females received saline. On the 30th day post‑birth, a social interaction test was performed on the offspring to confirm autistic‑like behavior. Offspring were divided into three subgroups: no exercise, mild exercise training, and moderate exercise training. Then the oxidative index of malondialdehyde (MDA) and the antioxidant indices of superoxide dismutase (SOD), total antioxidant capacity (TAC), and catalase in liver tissue were examined. The results of this study showed that both indices of sociability and social novelty decreased in the autism group. MDA levels in the liver of the autistic group increased, and moderate exercise training was shown to reduce the levels. Catalase and SOD activity as well as TAC levels decreased in the autism group, and moderate‑intensity exercise training was shown to increase the values. Parameters of hepatic oxidative stress were altered in VPA‑induced autism, and moderate‑intensity endurance exercise training was demonstrated to have beneficial effects on hepatic oxidative stress factors by modul ating the antioxidant/oxidant ratio.

In the central nervous system, long‑term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well‑being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met‑enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune‑derived plasma met‑enkephalin to establish a long‑term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation‑induced increases of plasma met‑enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.

Both cannabinoid and opioid receptors are involved in pain behavior. The administration of morphine and cannabis in rats has been shown to decrease thyroid weight and thyroid‑stimulating hormone (TSH) levels. We hypothesized that the third ventricle, due to its adjacency to the hypothalamus, is involved in the modulation of hypothalamic‑pituitary‑thyroid axis activity and descending pain pathways. The present study examined the effect of intra‑third ventricle administration of morphine and cannabis agents on the modulation of pain behavior in normal, hypothyroid (increased serum TSH), and hyperthyroid (decreased serum TSH) rats using the tail‑flick test. The results indicated that intra‑third ventricle injection of AM251 (CB1 receptor antagonist) caused hyperalgesia, while intra‑third ventricle administration of ACPA (CB1 receptor agonist) and morphine produced analgesia in normal, hypothyroid, and hyperthyroid rats. A non‑effective dose of morphine (0.5 μg/rat) did not attenuate hyperalgesia induced by an effective dose of AM251. Co‑injection of ACPA and morphine into the third ventricle induced anti‑nociceptive effect in normal, hypothyroid, and hyperthyroid rats. An isobolographic analysis demonstrated a synergistic effect between ACPA and morphine in the production of the anti‑nociceptive effect. Consequently, the third ventricle may modulate pain behavior induced by cannabinoid and opioid receptors via descending pain pathways in normal, hypothyroid, and hyperthyroid rats.

The potential of minocycline to protect against methylphenidate‑induced neurodegeneration has been extensively reported in the literature but the mechanism of action is still unknown. This study aims to determine the role of mitochondrial chain enzymes and redox homeostasis on the neuroprotective effects of minocycline in methylphenidate‑induced neurodegeneration. Wistar adult male rats were randomly assigned to the seven experimental groups: Group 1 received saline solution; Group 2 received methylphenidate (10 mg/kg, i.p.); Groups 3, 4, 5, and 6 received methylphenidate and minocycline for 21 days; Group 7 received minocycline alone. Cognition was evaluated with the Morris water maze test. Activity of the hippocampal mitochondrial quadruple complexes I, II, III and IV, mitochondrial membrane potential, adenosine triphosphate (ATP) levels, total antioxidant capacity, and reactive oxygen species were determined. Treatment with minocycline inhibited methylphenidate‑induced cognitive dysfunction. Minocycline treatment increased mitochondrial quadruple complex activities, mitochondrial membrane potential, total antioxidant capacity, and ATP levels in the dentate gyrus and cornu ammonis‑1 (CA1) areas of the hippocampus. Minocycline is likely to confer neuroprotection against methylphenidate‑induced neurodegeneration and cognition impairment by regulating mitochondrial activity and oxidative stress.

Crocin and Terminalia chebula (T. chebula) were proven to have neuroprotective effects. In this study, we evaluated the preventive effects of crocin and alcoholic extract of the T. chebula alone and in combination to examine their efficacy against chronic restraint stress (CRS)‑induced cognitive impairment, anxiety‑like behaviors, hippocampal synaptic plasticity deficit as well as neuronal arborization damage in the hippocampal CA1 neurons. Over 14 consecutive days, animals received crocin, T. chebula, or their combination (5 min before CRS). The elevated plus‑maze results showed that crocin and T. chebula alone and in combination treatment significantly increased the time spent in open arms, percentage of open arm entries, and head dipping as compared with the CRS group. Barnes maze results showed that administration of crocin and T. chebula alone and their combination significantly improves spatial memory indicators such as distance traveled, latency time to achieving the target hole, and the number of errors when compared to the CRS group. These learning deficits in CRS animals correlated with a reduction of long-term potentiation (LTP) in hippocampal CA1 synapses, which both T. chebula and crocin treatment improved field excitatory postsynaptic potentials (fEPSP) amplitude and fEPSP slope reduction induced by CRS. Golgi‑Cox staining showed that T. chebula and crocin treatment increased the number of dendrites and soma arbors in the CA1 neurons compared with the CRS group. Our results suggest that both T. chebula and crocin attenuated CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons. We found no significant difference between single treatments of T. chebula or crocin and their combination in protecting CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons.