Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aß-Oligomer-Induced Neurotoxicity.

Amyloid ß-peptide (Aß) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer's disease (AD). Aß oligomer (Aßo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aßo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants' neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aß-induced oxidative stress.

Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane.

α-Synuclein (αS), the causative protein of Parkinson's disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aß-Oligomer-Induced Neuronal Injury.

Amyloid-ß (Aß) is one of the causes of Alzheimer's disease (AD), damaging nerve membranes and inducing neurotoxicity. AD is more prevalent in female patients than in male patients, and women are more susceptible to developing AD due to the decline in estrogen levels around menopause. Raloxifene, a selective estrogen receptor modulator, exhibits protective effects by activating the transmembrane G-protein-coupled estrogen receptor (GPER). Additionally, raloxifene prevents mild cognitive impairment and restores cognition. However, the influence of raloxifene via GPER on highly toxic Aß-oligomers (Aßo)-induced neurotoxicity remains uncertain. In this study, we investigated the GPER-mediated neuroprotective effects of raloxifene against the neurotoxicity caused by Aßo-induced cytotoxicity. The impact of raloxifene on Aßo-induced cell damage was evaluated using measures such as cell viability, production of reactive oxygen species (ROS) and mitochondrial ROS, peroxidation of cell-membrane phospholipids, and changes in intracellular calcium ion concentration ([Ca2+]i) levels. Raloxifene hindered Aßo-induced oxidative stress and reduced excessive [Ca2+]i, resulting in improved cell viability. Furthermore, these effects of raloxifene were inhibited with pretreatment with a GPER antagonist. Our findings suggest that raloxifene safeguards against Aßo-induced neurotoxicity by modifying oxidative parameters and maintaining [Ca2+]i homeostasis. Raloxifene may prove effective in preventing and inhibiting the progression of AD.

The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aß Oligomers.

In Alzheimer's disease (AD), accumulation of amyloid ß-protein (Aß) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aß has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aß-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aß oligomers (Aßo), which include high-molecular-weight (HMW) Aßo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 µM) on Aßo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aßo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aßo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aßo exposure.

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aß-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-ß (Aß)-induced neuronal cytotoxicity. The effect of Cur or FA on Aß aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aß exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

Adult-onset Still's disease presenting with aseptic meningitis as the first symptom in an elderly patient.

•Neutrophilic meningitis is rarely observed in Adult onset Still's disease (AOSD).•AOSD-related meningitis has been observed in the AOSD course of young adults.•An elderly man showed neutrophilic meningitis as a first symptom of AOSD.•First-line therapy with steroid for bacterial meningitis complicated the diagnosis.•Hyperferritinemia led to the correct diagnosis of AOSD and AOSD-related meningitis.

Utility of thermographic measurements of laterality of body surface temperature to prevent misdiagnosis of acute Wallenberg's syndrome.

INTRODUCTION: Acute Wallenberg's syndrome (WS) is sometimes misdiagnosed as a nonstroke disease including auditory vertigo, and careful neurological examination is required for a precise diagnosis. Lateral difference of body surface temperature (BST) had been reported as a symptom of WS, although further details of this symptom are currently lacking. Our aim was to investigate the laterality of BST of patients with acute WS using thermography and the usefulness of thermography to detect acute WS. METHODS: Nine consecutive patients with new-onset acute WS and nine patients with acute pontine infarction, intended for a comparison, were enrolled. Using thermography, the BST of patients was measured and initially evaluated visually. Detailed BSTs were measured using dedicated software. We examined the relationship between BST and other clinical factors, including first diagnosis, clinical symptoms, and MRI findings. RESULTS: Four patients with WS (44.44%) were misdiagnosed with nonstroke disease and did not receive a thermography assessment at their first visit; in contrast, all acute pontine infarction patients were diagnosed with brain infarction. Eight patients with WS (89%) showed a laterality of BST at multiple sites, and three of eight patients showed a whole-body laterality of BST; in contrast, only two pontine infarction patients showed laterality of BST at one or two sites. These lateral BST differences were easily observed visually using thermography within two minutes. The BST laterality gradually decreased over time in almost all patients with WS. The infarction size in the WS patients with whole-body laterality of BST was craniocaudally larger than in the other patients, and the size was smallest in the patient showing no BST laterality. CONCLUSIONS: In contrast to acute pontine infarction patients, almost all patients with acute WS showed lateral BST differences, which was easily detected with thermography. Thermography may thus be a useful tool to prevent misdiagnosis of acute WS.

Usefulness Differs Between the Visual Assessment and Specific Binding Ratio of 123I-Ioflupane SPECT in Assessing Clinical Symptoms of Drug-Naïve Parkinson's Disease Patients.

Background: In clinical practice, assessment of the striatal accumulation in 123I-ioflupane single photon emission computed tomography (SPECT) is commonly performed calculating the specific binding ratio (SBR) for the whole striatum. On the other hand, visual assessment of striatal accumulation in the SPECT was recently established. However, correlations of visual assessment with motor and cognitive functions in Parkinson's disease (PD) have rarely been examined. Differences in the usefulness of these assessments at clinics are uncertain. Objective: We performed this study to compare correlations of cognitive and motor functions in drug-naive PD between the SBR and visual assessment using 123I-ioflupane SPECT. Methods: Cognitive and motor assessments and 123I-ioflupane SPECT were performed in 47 drug-naïve PD patients with Mini-mental State Examination scores of ≥25. Cognitive function was assessed using the total score and 6 subscores of the Montreal Cognitive Assessment (MoCA) and 10 separate subtests of the Neurobehavioral Cognitive Status Examination (COGNISTAT). Motor function was assessed using the Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale. Accumulation of 123I-ioflupane was determined by visual assessment based on five grades: 1, burst striatum; 2, egg-shaped; 3, mixed type; 4, eagle wing; 5, normal striatum; and by calculating SBR averaged for the bilateral striatum using the DaTView computer software commonly used in clinical practice. Each SPECT assessment was compared with each subscore for cognitive and motor assessments. Results: Spearman correlation analysis showed SBR was significantly correlated with the MoCA subscores of visuospatial function and attention, and with COGNISTAT subtests of attention. Visual assessment showed significant negative correlation with the Hoehn and Yahr scale. Mean score of postural instability in patients with visual grade of 1 was significantly higher than those in patients with visual grades of 2 and 3. Conclusion: Clinical symptoms reflected by 123I-ioflupane SPECT differ between the SBR and visual assessment. SBR reflects some cognitive functions, whereas a visual assessment grade of 1, which signifies decreased uptake of 123I-Ioflupane in the caudate nucleus, reflects postural instability. Thus, the caudate nucleus may play an important role in posture maintenance. Our results suggest that performing both assessments is of value.