Carvacrol and Thymol Attenuate Cytotoxicity Induced by Amyloid β25-35 Via Activating Protein Kinase C and Inhibiting Oxidative Stress in PC12 Cells (original) (raw)
Related papers
Basic and Clinical Neuroscience (BCN), 2022
We have reported that thymol and carvacrol can improve cognitive abilities in Alzheimer Disease (AD) rat models. However, the mechanism of their action is not yet fully understood. Recently, our in vitro results suggested that PC12 cell death induced by Aβ 25-35 can be protected by thymol and carvacrol via Protein Kinase C (PKC) and Reactive Oxygen Species (ROS) pathways. So, we hypothesize that the mechanisms of thymol and carvacrol in improving the learning impairment in the AD rat model may be related to their effects on PKC. So, the activity of PKC and protein expression levels of PKCα were examined in the hippocampal cells of the AD rat model. Methods: To examine the thymol and carvacrol effects, we performed a behavioral test in AD rat models induced by Aβ 25-35 neurotoxicity. To access the underlying mechanism of the protective effects, western blotting was performed with antibodies against PKCα. We also measured the PKC activity assay by Elisa. Histopathological studies were carried out in the hippocampus with Hematoxylin and Eosin (H&E) staining. Results: The escape latency increased in Aβ-received rats compared to the control group, and thymol and carvacrol reversed this deficit. Furthermore, these compounds could enhance the PKC activity and increase the PKCα expression ratio. Moreover, H&E staining showed that Aβ caused shrinkage of the CA1 pyramidal neurons. However, thymol and carvacrol treatments could prevent this effect of Aβ peptides. Conclusion: This study suggests that Amyloid-Beta (Aβ) results in memory decline and histochemical disturbances in the hippocampus. Moreover, these results revealed that thymol and carvacrol could have protective effects on cognition in AD-like models via PKC activation.
2021
Introduction: We have reported that thymol and carvacrol can improve cognitive abilities in Alzheimer's disease (AD) rat model. However, the mechanism of their action is not yet fully understood. Recently, our in vitro results suggested that PC12 cell death-induced by Aβ25-35 can be protected by thymol and carvacrol via PKC and ROS pathways. So, we hypothesize that the mechanisms of thymol and carvacrol in improving the learning impairment in AD rat model may be related to their effects on PKC. So, the activity of PKC and protein expression levels of PKCα was examined in the hippocampal cells of AD rat model. Methods: To examine thymol and carvacrol effects, we performed behavioral test in AD rat model induced by Aβ25-35 neurotoxicity. To access the underlying mechanism of protective effects, western blotting was performed with antibodies against PKCα. We also measured PKC activity assay by Elisa. Histopathological studies were carried out in hippocampus by hematoxylin & eosin (H&E). Results: It was shown that escape latency increased in Aβ-received rats compared to control group and thymol and carvacrol reversed this deficit. Furthermore, these compouds could enhance PKC activity, and increase the PKCα expression ratio. Moreover, H&E showed that Aβ caused shrinkage of the CA1 pyramidal neurons. However, thymol and carvacrol treatments could prevent this effect of Aβ peptides. Conclusions: This study suggests that Aβ results in memory decline and histochemical disturbances in hippocampus. Moreover, these results revealed that thymol and carvacrol could have protective effects on cognition in AD-like models via PKC activation.
Biomedicine & Pharmacotherapy, 2019
The progressive accumulation of amyloid beta (Aβ) peptide is neurotoxic and leads to Alzheimer's type dementia. Accumulation of Aβ has been associated with dysfunction of hypothalamic-pituitary-adrenal (HPA) axis and elevated pro-inflammatory cytokines. In this study, we investigated the effect of 1`δ-1`-acetoxyeugenol acetate (DAEA), isolated from Alpinia galanga (L.), on Aβ (25-35) induced neurodegeneration in mice. Mice were treated with three different doses of DAEA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) for 28 days. Aβ (25-35) was injected by intracerebroventricular (i.c.v.) injection on the 15th day of 28 days. Open field, water maze and stepdown inhibitory tests were performed on the 27th day to determine the habituation memory, spatial learning, and short-and long-term memory, respectively. Acetylcholinesterase (AChE), Corticosterone, biogenic amines (serotonin and dopamine), tumour necrosis factor-α (TNF-α), and antioxidant parameters such as superoxide dismutase, catalase, glutathione peroxidase and vitamin C were evaluated in brain homogenates after behavioural tests to ascertain the cognitive improvement through neuro-immune-endocrine modulation. The DAEA treatment with 25 mg/kg and 50 mg/kg resulted in significant (p < 0.001) improvement of habituation memory and step-down inhibitory avoidance task. In spatial learning, the cognitive improvement was significantly improved (p < 0.001) by reduction in escape latency. In the biochemical study, the significant (p < 0.001) reduction of AChE indicates the preeminent neuroprotection. Corticosterone and TNF-α were significantly (p < 0.01) reduced and biogenic amines were increased with antioxidant markers, which signify the potential influence of DAEA on neuroprotection. Our investigation revealed that the drug DAEA attenuates stress mediated through the HPA axis and regulates the neuroendocrine and neuroimmune function to improve the cognition. DAEA could be a potential lead candidate for the treatment of neurodegeneration.
Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies
Current Drug Target -CNS & Neurological Disorders, 2005
The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Aβ) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Aβ neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Aβ cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Aβ and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Aβ species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca 2+ dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, γand βsecretase inhibitors, Aβ clearance agents (Aβ immunization, disruption of Aβ fibrils, modulation of the cholesterol-mediated Aβ transport), nonsteroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.
BioMed Research International
Alzheimer’s disease (AD) could be considered a multifactorial neurodegenerative disorder characterized by the accumulation of theβ-amyloid-peptide (Aβ) within the brain leading to cognitive deficits, oxidative stress, and neuroinflammation. The present work was carried out to investigate the neuroprotective effect of (-)-cis-carveol (1% and 3%, for 21 days) against theβ-amyloid-peptide 1-42- (Aβ1-42-) induced AD. Twenty-five rats were divided into five groups (n=5/group): the first group—control (sham-operated); the second group—Aβ1-42 (1 mM) that received donepezil treatment (5 mg/kg, as the positive reference drug in the Y-maze and the radial arm maze tests); the third group—Aβ1-42 (1 mM); the fourth and fifth groups—Aβ1-42 (1 mM) that received (-)-cis-carveol treatment groups (1% and 3%). The results of this study demonstrated that (-)-cis-carveol improved Aβ1-42-induced memory deficits examined by using Y-maze and radial arm mazein vivotests. Also, the biochemical analyses of th...
Tacrine and donepezil attenuate the neurotoxic effect of Aβ(25-35) in rat PC12 cells
NeuroReport, 1998
THE effect of the cholinesterase inhibitors tacrine and donepezil on A(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10-7-10-6 M) to attenuate A(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10-5 M) and tubocurarine (10-5 M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease.
International Journal of Clinical Nutrition & Dietetics
carnitine, coenzyme Q10, polyphenols, ginkgo biloba, long chain polyunsaturated fatty acids-PUFAs) have been devoted a lot of attention [10,11]. In this paper we investigate the neuroprotective efficacy of docosahexaenoic acid (DHA), glutathione (GSH), phosphatidylcholine (PC), curcumin (CUR) and resveratrol (RES) given alone or in combination for thirty consecutive days as a preventive treatment in a well recognized mouse model of AD. This model consists in a unique intracerebroventricular (i.c.v.) injection of oligomeric amyloid-beta peptide 25-35 (Aβ 25-35) in mice [12] which is able to mimic both cognitive impairment and associated neuronal degeneration. Though Aβ1-40/42 peptides are considered as the major protagonists in the pathology, other small oligomeric fragments have been identified and among those, the highly toxic one is Aβ 25-35 [13,14] which is also endogenously present in AD human brain [15].
Vol 26, No 5, May , 2024
Objective: Trimethyltin (TMT) chloride is an organotin compound used in industry. It has been linked to generating reactive oxygen species (ROS), inflammatory processes, and neuronal death. Carvacrol is a monoterpene phenol found in the Lamiaceae plant family, modulating inflammatory conditions and necroptosis in neural tissue. This study aimed to investigate the neuroprotective effects of carvacrol in a rat model of hippocampal neuronal injury induced by TMT. Materials and Methods: In this experimental study, sixty male Wistar rats were randomly divided into five groups (n=12): group 1 receiving saline, group 2 received dimethyl sulfoxide (DMSO) as a vehicle for 21 days, group 3 receiving a single dose of TMT (8 mg/kg) and groups 4 and 5 receiving carvacrol 40 and 70 mg/kg daily for 21 days after a single dose of TMT. All injections were intraperitoneal (I.P.). Caspase-3, Bax, Bcl-2, and Bdnf gene expression and the number of pyknotic neurons in the hippocampus were quantified. Spatial memory was assessed with a radial arm maze. Results: Statistical analysis of histological data revealed the carvacrol significantly attenuated cognitive dysfunction and the number of pyknotic neurons in the hippocampal CA1 region of rats treated with TMT. Based on real-time polymerase chain reaction (PCR), carvacrol modulated the expression of genes involved in apoptosis (Bax and Caspase-3) and upregulated anti-apoptotic (Bcl-2) and brain derived neurotrophic factor (Bdnf) genes in the hippocampal tissue. Conclusion: These findings revealed neuroprotective effects of carvacrol which might be mediated by apoptotic and anti-apopetotic factors.
SK-PC-B70M confers anti-oxidant activity and reduces Aβ levels in the brain of Tg2576 mice
Brain Research, 2009
B70M is an oleanolic-glycoside saponin-enriched fraction derived from the root of Pulsatilla koreana. Recently, it was reported that hederacolchiside-E is an active ingredient of SK-PC-B70M that confers a neuroprotective effect against the cytotoxicity induced by Aβ(1-42) in SK-N-SH neuroblastoma cells. SK-PC-B70M improves scopolamine-induced impairments of spatial working memory in rats. In the present study, we investigated whether SK-PC-B70M has a beneficial effect on the Tg2576 murine model of Alzheimer's disease. ELISA analysis revealed that the levels of soluble and insoluble forms of Aβ(1-42) in Tg2576 mice fed SK-PC-B70M (2000 ppm) from 11 months to 16 months of age were reduced to, respectively, 66% and 79% of the control Tg2576 mice. Anti-Aβ antibody-stained brain sections of Tg2576 mice with SK-PC-B70M (2000 ppm) consistently showed a reduction in plaque formation in the brain. Western blot analyses showed altered expressions of various cellular factors, such as up-regulation of transthyretin, phospho-ERK, and phospho-CREB in the brain treated with SK-PC-B70M. SK-PC-B70M suppressed the neuronal toxicity induced by H 2 O 2 in primary cortical culture. Moreover, biochemical and immunohistochemical analyses showed that the levels of malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), oxidized by-products of lipid peroxidation, were notably reduced in the hippocampus of Tg2576 mice treated with SK-PC-B70M compared with the Tg2576 control. These results suggest that SK-PC-B70M attenuates AD-like pathology in the brain of Tg2576 mice.
Molecular and Cellular Biochemistry, 2012
Beta-amyloid (Ab) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and compounds that can prevent pathways of Ab-induced neurotoxicity may be potential therapeutic agents for treatment of AD. This study examined the hypothesis that thymoquinone (TQ) would reduce oxidative stress and mitochondrial dysfunction in differentiated pheochromocytoma (PC 12) cells exposed to Ab fragment 25-35 (Ab 25-35). To test this hypothesis, Ab was used to induce an in vitro model of AD in differentiated PC 12 cell line of rat. After 24 h of exposure with Ab 25-35 , a significant reduction in cell viability and mitochondrial membrane potential (MMP) was observed. In addition, a significant elevation in the TBARS content and nitric oxide (NO) and activity of acetylcholine esterase (AChE) was observed which was restored significantly by TQ pretreatment. Furthermore, TQ also ameliorated glutathione and its dependent enzymes (glutathione peroxidase, glutathione reductase) which were depleted by Ab 25-35 in PC 12 cells. These results were supported by the immunocytochemical finding that has shown protection of cells by TQ from noxious effects of Ab 25-35. These results indicate that TQ holds potential for neuroprotection and may be a promising approach for the treatment of neurodegenerative disorders including AD.