ABSTRACT
Crocetin, the aglycone of crocin, is a carotenoid found in fruits of gardenia (Gardeina jasminoides Ellis) and saffron (Crocus sativus L.). We investigated the protective effects of crocetin against ultraviolet-A (UV-A)-induced skin damage and explored the underlying mechanism. Human skin-derived fibroblasts cells (NB1-RGB) were damaged by exposure to UV-A irradiation (10J/cm(2)). Crocetin protected these cells against cell death and reduced the production of reactive oxygen species induced by UV-A irradiation. Crocetin treatment also suppressed induction of caspase-3 activation by UV-A irradiation. The effects of crocetin against oxidative stress were also examined by imaging of Keap1-dependent oxidative stress detector (OKD) mice. UV-A irradiation upregulated oxidative stress in the OKD mice skin, while crocetin administration (100mg/kg, p.o.) ameliorated this oxidative stress. Crocetin administration also decreased lipid peroxidation in the skin. These findings suggest that crocetin its observed protective effects against UV-A induced skin damage by reducing reactive oxygen species production and cell apoptosis.
Subject(s)
Antioxidants/pharmacology , Carotenoids/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/radiation effects , Radiation-Protective Agents/pharmacology , Skin/cytology , Ultraviolet Rays/adverse effects , Animals , Autophagy/drug effects , Autophagy/radiation effects , Cell Death/drug effects , Cell Death/radiation effects , Crocus/chemistry , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/radiation effects , Lipid Peroxidation/drug effects , Lipid Peroxidation/radiation effects , Male , Mice , Reactive Oxygen Species/metabolism , Skin/drug effects , Skin/metabolism , Skin/radiation effects , Vitamin A/analogs & derivativesABSTRACT
Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. However, the etiology of the reduction in dopaminergic neurons remains unclear. Recently, it has been suggested that oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in neuronal cell death in the pathology of Parkinson's disease. Furthermore, it has been suggested that some existing anti- Parkinson's disease drugs have protective effects against cell death. Among these, zonisamide exerts neuroprotective effects partly by modulating ER stress. Elucidating the involvement of ER stress in in vitro and in vivo Parkinson's disease models and investigating the mechanisms against ER stress will contribute to the search for new therapeutic agents for Parkinson's disease.
Subject(s)
Endoplasmic Reticulum Stress/physiology , Parkinson Disease/metabolism , Animals , Antiparkinson Agents/pharmacology , Antiparkinson Agents/therapeutic use , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Endoplasmic Reticulum Stress/drug effects , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Substantia Nigra/drug effects , Substantia Nigra/metabolismABSTRACT
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by cognitive dysfunction and neuronal cell death in the hippocampus and cerebral cortex. Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptides. GLP-1-associated medicines are widely used as treatments for type 2 diabetes. In addition, they have been shown to ameliorate pathology in AD mouse models. Here, we investigated the effects of GLP-1 on different stressors in murine hippocampal HT22 cells. GLP-1 (7-36) prevented H2O2-, l-glutamate-, tunicamycin-, thapsigargin-, and amyloid ß1-42-induced neuronal cell death in a concentration-dependent manner. GLP-1 (7-36) treatment for 1 h significantly increased phosphorylated Akt and extracellular signal-regulated kinase 1 and 2 (ERK1/2) when compared with vehicle-treatment. These results suggest that GLP-1 (7-36) is protective against these stressors via activation of survival signaling molecules, such as Akt and ERK1/2 in HT22 cells. In conclusion, GLP-1 and activators of the GLP-1 receptor might be useful targets for the treatment of AD.
Subject(s)
Amyloid beta-Peptides/administration & dosage , Glucagon-Like Peptide 1/administration & dosage , Hippocampus/physiology , MAP Kinase Signaling System/physiology , Oxidative Stress/physiology , Peptide Fragments/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , Animals , Apoptosis/drug effects , Apoptosis/physiology , Cell Line , Cell Survival/drug effects , Cell Survival/physiology , Drug Interactions , Hippocampus/drug effects , Mice , Neuroprotective Agents/administration & dosage , Oxidative Stress/drug effectsABSTRACT
BACKGROUND: Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. Previously, we reported that DGKß knockout (KO) mice showed mania-like behaviors such as hyperactivity, reduced anxiety, and cognitive impairment. Furthermore, lithium ameliorated the hyperactivity and reduced anxiety of DGKß KO mice. In this study, we investigated the effects of the clinically active antimanic drugs valproate and olanzapine on the abnormal behaviors of DGKß KO mice. METHODS: Valproate (100mg/kg/day) and olanzapine (1mg/kg/day) were administered intraperitoneally. Following drugs treatments, behavioral tests were performed to investigate locomotor activity, anxiety levels, and cognitive function of the mice. RESULTS: A single treatment of valproate and olanzapine did not ameliorate the hyperactivity or abnormal anxiety level of DGKß KO mice. Chronic treatment with valproate and olanzapine significantly decreased locomotor activity and abnormal anxiety levels of DGKß KO mice. Additionally, valproate also ameliorated cognitive function of DGKß KO mice. CONCLUSION: These results suggest that the abnormal behaviors of DGKß KO mice is responsive to antimanic drugs, and that DGKß KO mice are useful as an animal model of mania.
Subject(s)
Anxiety/drug therapy , Benzodiazepines/therapeutic use , Cognition Disorders/drug therapy , Diacylglycerol Kinase/deficiency , Diacylglycerol Kinase/genetics , Maze Learning/drug effects , Motor Activity/drug effects , Valproic Acid/therapeutic use , Animals , Anxiety/genetics , Benzodiazepines/pharmacology , Cognition Disorders/genetics , Disease Models, Animal , Drug Therapy, Combination , Male , Mice , Mice, Knockout , Motor Activity/genetics , Olanzapine , Valproic Acid/pharmacologyABSTRACT
Zonisamide has been reported to have protective effects on epilepsy and Parkinson׳s disease and to work via various mechanisms of action, such as inhibition of monoamine oxidase-B and enhancement of tyrosine hydroxylase. Recently, it has been suggested that zonisamide itself shows neuroprotective actions. Therefore, in the present study we investigated the neuroprotective effects of zonisamide against endoplasmic reticulum (ER) stress. We used human neuroblastoma (SH-SY5Y) cells and investigated the protective effects of zonisamide against tunicamycin- and thapsigargin-induced neuronal cell death. In addition, we investigated the effect of zonisamide against 1-methyl-4-phenylpyridinium (MPPâº)-induced cell death and the mechanism of protection against ER stress. In vivo, we investigated the effect of zonisamide (20 mg/kg, p.o.) in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson׳s disease. Zonisamide not only suppressed MPPâº-induced cell death, but also inhibited ER stress-induced cell death and suppressed the expression of ER stress-related factors such as C/EBO homologous protein (CHOP) in vivo. Furthermore, zonisamide inhibited the activation of caspase-3 in vitro. These results suggest that zonisamide affected ER stress via caspase-3. We think that ER stress, particularly the mechanism via caspase-3, is involved in part of the neuroprotective effect of zonisamide against the experimental models of Parkinson׳s disease.
