The functional role of the pulvinar in discriminating between objective and subjective cognitive impairment in major depressive disorder.

INTRODUCTION: Emotionally driven cognitive complaints represent a major diagnostic challenge for clinicians and indicate the importance of objective confirmation of the accuracy of depressive patients' descriptions of their cognitive symptoms. METHODS: We compared cognitive status and structural and functional brain connectivity changes in the pulvinar and hippocampus between patients with total depression and healthy controls. The depressive group was also classified as "amnestic" or "nonamnestic," based on the members' subjective reports concerning their forgetfulness. We then sought to determine whether these patients would differ in terms of objective neuroimaging and cognitive findings. RESULTS: The right pulvinar exhibited altered connectivity in individuals with depression with objective cognitive impairment, a finding which was not apparent in depressive patients with subjective cognitive impairment. DISCUSSION: The pulvinar may play a role in depression-related cognitive impairments. Connectivity network changes may differ between objective and subjective cognitive impairment in depression and may play a role in the increased risk of dementia in patients with depression.

EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line.

Background: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes. Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy. Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels. Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process. Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases.

Infection with COVID-19 is no longer a public emergency: But what about degenerative dementia?

Although no longer considered a public health threat, post-COVID cognitive syndrome continues to impact on a considerable proportion of individuals who were infected with COVID-19. Recent studies have also suggested that COVID may be represent a critical risk factor for the development of Alzheimer's disease (AD). We compared 17 COVID patients with 20 controls and evaluated the effects of COVID-19 on general cognitive performance, hippocampal volume, and connections using structural and seed-based connectivity analysis. We showed that COVID patients exhibited considerably worse cognitive functioning and increased hippocampal connectivity supported by the strong correlation between hippocampal connectivity and cognitive scores. Our findings of higher hippocampal connectivity with no observable hippocampal morphological changes even in mild COVID cases may be represent evidence of a prestructural compensatory mechanism for stimulating additional neuronal resources to combat cognitive dysfunction as recently shown for the prodromal stages of degenerative cognitive disorders. Our findings may be also important in light of recent data showing that other viral infections as well as COVID may constitute a critical risk factor for the development of AD. To our knowledge, this is the first study that investigated network differences in COVID patients, with a particular focus on compensatory hippocampal connectivity.

Protective and Therapeutic Role of Ginkgo Biloba Extract Through TRPV1 Channels in an in Vitro Alzheimer's Disease Model.

Introduction: The effect of Ginkgo biloba (GB) on mitochondria-dependent TRPV1 ion channels in neuroblastoma cells was investigated by creating an Alzheimer's disease (AD) model. Methods: Okadaic acid was applied on SH-SY5Y cells to create an AD model. After cellular differentiation, the study was organized with the seven main groups, examining the effect of GB on calcium depended TRPV1 channels in neuroblastoma cells AD, has been established in vitro. Results: The higher Ca2+ concentration was detected in the GB+AD, AD and AD+GB groups when compared with the control (p<0.001). The Ca2+ level was lower in GB+AD and AD+GB groups than in the AD group (p<0.001). Also, cytosolic Ca2+ concentration was lower in the GB+AD than in the AD+GB group (p<0.05), the apoptosis and intracellular reactive oxygen species (ROS) values were higher in the GB+AD, AD and AD+GB groups than in the control (p<0.001). The apoptosis and intracellular ROS values were higher in AD group than in the GB+AD and AD+GB group (p<0.001) and the apoptosis level was higher in AD+GB group than GB+AD group (p<0.001) and the mitochondrial depolarization, caspase 3 and caspase 9 levels were higher in the GB+AD, AD and AD+GB groups when compared to the control group (p<0.001). Also, the values were lower in the GB+AD group, AD group and AD+GB groups when compared with the GB+AD+capsazepine group, AD+capsazepine group and AD+GB+capsazepine respectively (p<0.001). Conclusion: These results show us that GB has a protective effect besides its therapeutic effect in Alzheimer's disease via TRPV1 channel.

Prognostic Factors For Functional Outcome in Patients with Mesencephalic Hemorrhage.

Introduction: Mesencephalic hemorrhage (MH) is a rare presentation of spontaneous intraparenchymal hemorrhage. This study aims to evaluate prognostic parameters of the MH outcome. Methods: We conducted an extensive search in the literature for cases with spontaneous, isolated mesencephalic hemorrhage. The study was conducted according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Sixty-two eligible cases have been reported in the literature as proven by CT or MRI, and to these, we added six cases confirmed by MRI. The modified Rankin Scale (mRS) was dichotomized into two groups as the favorable outcome (FO; score, 0-2) and unfavorable outcome (UO; score, 3-6). Results: Of the 68 patients studied, 26 (38%) presented with normal consciousness, 22 (32%) with lethargy , and 20 (29%) with stupor or coma. There was no cause of hemorrhage in 26 (65%) patients with FO and 12 (43%) with UO (p=0.059). In univariate analyses, neither arteriovenous malformations (p=0.33) nor cavernomas (p=0.19) were associated with outcome. Multiple logistic regression analysis revealed that hypertension (OR, 51.22; CI95%, 1.92-1370.24; P=0.019), consciousness (OR, 133.54; CI95%, 1.61-1113.3; P=0.03), NIHSS at admission (OR, 57.23; CI95%, 2.87-1141.2; p=0.008), and ventrodorsal hemorrhage size (≥1 cm) (OR, 61.83; CI95%, 2.15-1779.2; p=0.016) were significantly associated with UO. Three months after stroke, 40 patients (59%) had FO, 28 (41%) had UO, and 8 (12%) died. Conclusion: These results suggest that ventrodorsal size of hemorrhage and clinical severity at stroke onset are possible predictors of functional outcome after mesencephalic hemorrhage.

Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial.

BACKGROUND: Alzheimer's disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. METHODS: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. RESULTS: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. CONCLUSION: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.

Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.

BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. METHODS: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. FINDINGS: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. INTERPRETATION: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

Potential Effects of Melatonin on TRPA1 Channels in the Prevention and Treatment of Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) is the most common cause of dementia and is defined as a progressive neurodegenerative disease. Main clinical features of AD are progressive impairment in learning and memory loss. Several studies have indicated that mitochondria play a critical role in the pathogenesis of AD. In this study, we investigated the effect of melatonin on mitochondria-dependent TRPA1 ion channels in neuroblastoma cells by creating an in vitro model of Alzheimer's disease. Methods: Okadaic acid was applied to SH-SY5Y (human neuroblastoma cell line) cells to create an AD model. After cellular differentiation, the following 7 main groups were created: Group 1 (Control), Group 2 (Mel+AD), Group 3 (Mel+AD+AP18), Group 4 (AD), Group 5 (AD+AP18), Group 6 (AD+Mel), and Group 7 (AD+Mel+AP18), and Alzheimer's disease was determined in vitro by examining the effect of melatonin on calcium-dependent TRPA1 channels in neuroblastoma cells. Results: The Ca2+concentration was greater in the melatonin+AD, AD and AD+melatonin groups than in the control (p<0.001). However, there was no statistically significant difference between Mel+AD+AP18, AD+Mel+AP18 and the control. We determined that Ca2+ levels were lower in the melatonin+AD and AD+melatonin groups than in the AD group (p<0.001 and p<0.05). Additionally, cytosolic Ca2+ concentrations were found to be lower in the melatonin+AD group than in the AD+melatonin group (p<0.05). In evaluating the apoptosis and oxidative stress levels, we found that the apoptosis and intracellular ROS values were higher in the melatonin+AD, AD and AD+melatonin groups than in the control (p<0.001). In this respect, the mitochondrial depolarization and caspase-3 and caspase-9 levels were higher in the melatonin+AD, AD and AD+melatonin groups than in the control group (p<0.001). Additionally, the mitochondrial depolarization, caspase-3 and caspase-9 values were higher in the AD group than in the melatonin+AD and AD+melatonin groups (p<0.001), while mitochondrial depolarization and caspase-3 levels were lower in the melatonin+AD group than in the AD+melatonin group (p<0.001). However, in the same groups, there was no statistically significant difference in caspase-9 results. Additionally, the caspase-9 values were lower in the melatonin+AD group, AD group and AD+melatonin groups than in the melatonin+AD+AP18, AD+AP18 and AD+melatonin+AP18 groups, respectively (p<0.001 and p<0.05). Conclusion: Our results suggest that melatonin may be an effective option in the treatment and prophylaxis of Alzheimer's disease by reducing cytosolic Ca2+ concentration, apoptosis and intracellular ROS through TRPA1 channels.

The involvement of TRPV4 on the hypoxia-induced oxidative neurotoxicity and apoptosis in a neuronal cell line: Protective role of melatonin.

The hypoxia (HYPX)-mediated excessive generation of mitochondrial free reactive oxygen species (mROS) and the overload Ca2+ influx via the inhibition of TRPV4 are controlled by the treatment of antioxidants. However, the molecular mechanisms underlying melatonin (MLT)'s neuroprotection remains elusive. We investigated the role of MLT via modulation of TRPV4 on oxidative neurodegeneration and death in SH-SY5Y neuronal cells. The SH-SY5Y cells were divided into five groups as follows: control, MLT (1 mM for 2 h), HYPX (200 µM CoCl2 for 24 h), HYPX + MLT, and HYPX + TRPV4 blockers (ruthenium red-1 µM for 30 min). The HYPX caused to the increase of TRPV4 current density and overload Ca2+ influx with an increase of mitochondrial membrane potential and mROS generation. The changes were not observed in the absence of TRPV4. When HYPX exposure and TRPV4 agonist (GSK1016790A)-induced TRPV4 activity were inhibited by the treatment of ruthenium red or MLT, the increase of mROS, lipid peroxidation, apoptosis, Zn2+ concentrations, TRPV4, caspase -3, caspase -9, Bax, and Bcl-2 expressions were restored via upregulation of reduced glutathione, glutathione peroxidase, and total antioxidant status. The levels of apoptosis and cell death in the cells were enriched with increases of caspase -3 and -9 activations, although they were decreased by MLT treatment. In conclusion, the treatment of MLT modulates HYPX-mediated mROS, apoptosis, and TRPV4-mediated overload Ca2+ influx and may provide an avenue for protecting HYPX-mediated neurological diseases associated with the increase of mROS, Ca2+, and Zn2+ concentration.

Topological network mechanisms of clinical response to antidepressant treatment in drug-naive major depressive disorder.

AIM: There is rapidly increasing evidence that remission of MDD is associated with substantial changes in functional brain connectivity. These New data have provided a holistic view on the mechanism of antidepressants on multiple levels that goes beyond their conventional effects on neurotransmitters. METHOD: The study was approved by the Local Ethics Committee of Istanbul Medipol University (10840098-604.01.01-E.65129) and followed the Helsinki Declaration principles. In our study, we have evaluated the effect of six weeks of treatment with antidepressants (escitalopram and duloxetine), and tested the underlying brain functional connectivity through a Graph analysis approach in a well-defined first-episode, drug-naive, and non-comorbid population with MDD. RESULTS: Beyond indicating that there was a significant correlation between the antidepressant response and topological characteristics of the brain, our results suggested that global rather than regional network alterations may be implicated in the antidepressant effect. CONCLUSION: Despite the small-sample size and non-controlled study design, our study provides important and relevant clinical data regarding the underlying mechanisms of the antidepressants on topological dynamics in the human brain.

Clostridium botulinum neurotoxin A induces apoptosis and mitochondrial oxidative stress via activation of TRPM2 channel signaling pathway in neuroblastoma and glioblastoma tumor cells.

BACKGROUND: The Clostridium botulinum neurotoxin A (BTX) is a polypeptide produced by the bacterium Clostridium botulinum. In addition to the therapeutic actions of BTX against pain and neuromuscular disorders, it is acted as anticancerogenic effect through excessive mitochondria reactive oxygen species (ROS) production, apoptosis, and caspase activations. The TRPM2 cation channel is activated by ROS and ADP-ribose and it is inhibited by 2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl) anthranilic acid (ACA). The aim of this study was an investigation of involvement BTX-induced TRPM2 activation on the mitochondria ROS production and apoptosis levels in the DBTRG glioblastoma and SH-SY5Y neuroblastoma tumor cells. MATERIAL AND METHODS: The DBTRG and SH-SY5Y cells were divided into four groups as control, BTX (5 IU for 24 h), BTX + ACA (25 µM for 30 min), and BTX + 2-APB (100 µM for 30 min). RESULTS: BTX treatment increased mitochondrial membrane depolarization (JC-1), mitochondrial (MitROS), and cytosolic (DHR123 and DCFH-DA) ROS levels, neuronal death (propidium iodide/Hoechst) rate, caspase -3, and -9 levels in the BTX group, although their levels were diminished in the BTX + ACA and BTX + 2-APB groups. The ACA and 2-APB treatments also decreased BTX-induced increase of TRPM2 cytosolic free Ca2+ concentration in the glioblastoma and neuroblastoma cell death. CONCLUSIONS: BTX caused neuroblastoma and glioblastoma tumor cell death by activating the mitochondria ROS production via stimulating TRPM2 signaling pathways. BTX may serve as a potential therapeutic target via activation of TRPM2 for treating glioblastoma and neuroblastoma cells.

Paracetamol alters empathy scores in healthy and headache subjects: Functional MRI correlates.

INTRODUCTION: Although previous evidence suggest that paracetamol decreases psychological reactivity in healthy subjects, there is still no confirmed correlation between the empathy scores and brain activity in healthy and headache patients after paracetamol treatment. MATERIAL AND METHODS: The study group included 16 patients with tension-type headache, and 12 healthy age-and sex-matched controls. After a detailed neurological examination Positive and Negative Affect Schedule (PANAS) and Empathy for Pain Scale (EPS) were applied to all subjects. Next, 1000 mg paracetamol tablet was administered orally, after administration of paracetamol, EPS were repeated, and fMRI was performed to all subjects. RESULTS: We have revealed increased empathy scores in the headache group after the paracetamol treatment which were associated with significant alterations in brain regions which play a critical role in the processing of empathy. DISCUSSION: The observed neuroimaging and clinical difference between healthy and headache subjects could be related to the fact that pain perception in healthy subjects might differ in some aspects from the mechanisms of empathy in headache-experienced patients. CONCLUSION: To the best of our knowledge, this is the first study that evaluated the paracetamol treatment and neural networks' correlation with pain empathy in healthy and headache individuals.

Electrophysiological findings of Turkish patients with restless legs syndrome.

We aimed to investigate changes in electrophysiological findings in Turkish patients with restless legs syndrome (RLS), including F-wave latency (FWL), peripheral silent period (PSP), and Hoffmann reflex. The study took place in a university hospital in Turkey and involved 30 newly diagnosed RLS patients and 30 healthy controls who were matched for age and gender. Participant's demographics (age, gender, weight, and height), laboratory findings, and electrophysiological test outcomes were gathered and analyzed. There was no significant difference in the FWL of the median and ulnar nerves, whereas the H-wave maximum amplitude and H/M ratio were significantly higher in the RLS patients than in the controls at rest. All of the PSP parameters were similar between patients and controls for the abductor pollicis brevis and gastrocnemius muscles. However, for the tibialis anterior muscle, all the PSP duration parameters were shorter in the RLS patients, whereas the PSP latency parameters were similar. The data suggest that there may be a reduction in spinal segmental inhibition at the L4-L5-S1 level, but the mechanisms of inhibition at the L4-L5 and S1 levels may be different; furthermore, there may be no pathology in the peripheral nerves. Further prospective studies with larger cohorts are now needed to evaluate the pathophysiology of RLS with different neurophysiological assessment tools.