RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Curcumina , Neuroblastoma , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Membrana Celular/metabolismo , Curcumina/farmacología , Fosfolípidos/farmacologíaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Curcumina , Neuroblastoma , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Línea Celular Tumoral , Ácidos Cumáricos , Curcumina/farmacología , Curcumina/uso terapéutico , Humanos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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.
RESUMEN
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.
RESUMEN
BACKGROUND: Atherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes. METHODS: U937 cells at densities of 1 × 106 cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 µg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1ß only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits. RESULTS: LPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1ß alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1ß and simultaneous treatment with IL-1ß and linagliptin. CONCLUSIONS: Linagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.
RESUMEN
BACKGROUND: Effects of dopaminergic medication on executive function in patients with Parkinson's disease (PD) are inconsistent. OBJECTIVE: We examined the effect of dopaminergic medication on executive function in 24 drug-naïve PD patients (de novo group) and in 21 PD patients on chronic dopaminergic medication (chronic medication group). METHODS: PD patients without dementia were included in this study. For the de novo group patients, dopaminergic medication was initiated, and the dose was increased to improve motor symptoms. For the chronic medication group patients, dopaminergic medication was adjusted to relieve clinical problems. All participants were tested prior to and at 4-7 months after the drug initiation/adjustment. Executive function was assessed by using the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Motor function was assessed by using the Unified Parkinson's Disease Rating Scale (UPDRS; part III). Improvement in executive function was compared with a simultaneous change in levodopa equivalent doses (LED) of dopaminergic medication and with improvement in motor functions. RESULTS: The mean standardized BADS scores showed no significant improvement in both the groups. In the de novo group, percent improvement in the standardized BADS scores showed a significant positive correlation with the LED, but not with percent improvement in UPDRS part III. In the chronic medication group, percent improvement in the standardized BADS scores was negatively correlated with change in the LED, but not with percent improvement in UPDRS part III. Multiple regression analysis using improvement in the standardized BADS score as a dependent variable and patient's background factors (ie, age, education, disease duration, and motor and executive assessments at baseline) as independent variable showed that improvement in the executive assessment is significantly correlated with the LED only in the de novo group. CONCLUSION: Effects of dopaminergic drug adjustment on executive function differ according to the patient's clinical stage and depend on LED in de novo stage.
RESUMEN
Background: Selegiline enhances the patient's endogenous dopamine by inhibiting dopamine metabolism. The efficacy of selegiline monotherapy for drug-naïve Parkinson's disease (PD) patients may depend on the degree of dopaminergic neuronal degeneration. 123I-Ioflupane single photon emission computed tomography (SPECT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy are diagnostic methods to assess the pharmacological and pathological changes in PD. Objective: We examined the utility of these imaging methods to predict the efficacy of selegiline monotherapy for motor symptoms in drug-naïve PD patients. Methods: We observed the efficacy of selegiline monotherapy in 28 drug-naïve PD patients and compared the improvement in motor function and the imaging findings. These patients received selegiline monotherapy, and the amount was increased to the optimal dose in clinical practice. Motor function was assessed using the Unified Parkinson's Rating Scale (UPDRS) at baseline and at the stable dose. Imaging was performed before treatment, and the striatal Specific Binding Ratio (SBR) of the 123I-Ioflupane SPECT and the Heart-to-Mediastinum (H/M) ratio of the 123I-MIBG myocardial scintigraphy were calculated. Both ratios were compared with improvements in scores for motor assessment using Pearson's correlation coefficient. Results: The mean UPDRS part III score significantly improved with at least 5.0 mg/day of selegiline. Further dose escalation did not improve the mean motor score. The percent improvement in the motor score from baseline showed a significant negative correlation with the SBR of average of the right and left striatum, but not with the H/M ratio. Multiple regression analysis using patient's background factors showed that percent improvement in the UPDRS part III score directly correlate with the SBR (p = 0.04), but not with the age (p = 0.72), disease duration (p = 0.31), baseline UPDRS part III (p = 0.77) and the drug dose (p = 0.26). Conclusion: PD patients with a lower accumulation of 123I-Ioflupane in the striatum can have greater improvement with selegiline monotherapy.
RESUMEN
BACKGROUND: Dopaminergic drugs, the gold standard for motor symptoms, are known to affect cognitive function in Parkinson's disease (PD) patients. OBJECTIVE: We compared the effects of dopaminergic treatment on motor and cognitive function in drug-naïve patients. METHODS: Dopaminergic medication (levodopa, dopamine agonist, selegiline) was given to 27 drug-naïve PD patients and increased to a dose optimal for improved motor symptoms. Patients were tested prior to, and 4-7 months after, drug initiation. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). Cognitive function was assessed using both the Japanese version of the Montreal Cognitive Assessment (MoCA-J) and the Neurobehavioral Cognitive Status Examination (COGNISTAT-J). Improvements from baseline for both motor and cognitive assessment were compared. RESULTS: Mean score of all motor assessments (UPDRS total score of Parts II and III, and sub-scores of tremor, rigidity, bradykinesia, gait, and postural instability) and certain cognitive assessments (MoCA-J total score and subscore of delayed recall) significantly improved with dopaminergic medication. Gait score improvement showed significant positive correlation with improvement in MoCA-J language domain and in language-comprehension subtests of COGNISTAT-J using Spearman's correlation coefficients. Furthermore, multiple regression analysis showed gait score improvement significantly correlated with improvements in the subtests of language-comprehension in COGNISTAT-J. CONCLUSION: There is correlated improvement in both gait and language function in de novo PD patients in response to dopaminergic drugs. Gait and language dysfunction in these patients may share a common pathophysiology linked to dopamine deficits.