Investigating the mechanism of antiepileptogenic effect of apigenin in kainate temporal lobe epilepsy: possible role of mTOR.

Clarifying the underlying mechanisms of epileptogenesis is important in preventing the progression of chronic epilepsy. In epilepsy, the mTOR (mammalian target of rapamycin) pathway plays a critical role in mediating the mechanism of epileptogenesis. In this study, we investigate whether apigenin can exert antiepileptogenic effects through the inhibition of mTOR in the kainate model of epilepsy. For assessing the antiepileptogenic effect of apigenin in kainic acid (KA)-induced temporal lobe epilepsy (TLE) model, apigenin at a dose of 50 mg/kg was administrated by gavage for 6 days. An intracranial electroencephalogram (iEEG) was performed to confirm the establishment of status epilepticus. BrdU was used to detect neurogenesis in the CA3, and dentate gyrus and mossy fiber sproutings were assessed by Timm staining. The expression of mTOR was quantified via western blot. We found that apigenin-pretreatment had a significant inhibitory effect on neural cell death, spontaneous seizure spikes, aberrant neurogenesis, mTOR hyperactivity, and aberrant mossy fiber sprouting. Overall, these results suggest that apigenin has an antiepileptogenic effect and may be a useful target for inhibiting mTOR hyperactivity in epilepsy.

Evaluation the cognition-improvement effects of N-acetyl cysteine in experimental temporal lobe epilepsy in rat.

Memory impairment is a critical issue in patients with temporal lobe epilepsy (TLE). Neuronal loss within the hippocampus and recurrent seizures may cause cognitive impairment in TLE. N -acetyl cysteine (NAC) is a sulfur-containing amino acid cysteine that is currently being investigated due to its protective effects on neurodegenerative disorders. NAC was orally administrated at a dose of 100 mg/kg for 8 days (7-day pretreatment and 1-day post-surgery). Neuronal viability, mTOR protein level, and spatial memory were detected in the kainite temporal epilepsy model via Nissl staining, western blot method, and Morris water maze task, respectively. Results showed that NAC delayed seizure activity and ameliorated memory deficit induced by Kainic acid. Histological analysis showed that NAC significantly increased the number of intact neurons in CA3 and hilar areas of the hippocampus following the induction of epilepsy. NAC also modulated the mTOR protein level 5 days after epilepsy compared to the KA-induced group. CONCLUSION: These results suggest that NAC improved memory impairment via anticonvulsant and neuroprotective activity and, in all probability, by lowering the level of mTOR.

Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.

Understanding the underlying molecular mechanisms involved in epilepsy is critical for the development of more effective therapies. It is believed that mTOR (Mechanistic Target of Rapamycin kinases) activity and the mitochondrial dynamic balance change during epilepsy. mTOR affects mitochondrial fission by stimulating the translation of mitochondrial fission process 1 (MTFP1). In This study, the protective role of N-acetylcysteine was studied in temporal lobe epilepsy (TLE) through the regulation of mTOR and mitochondrial dynamic proteins. Rats received N-acetylcysteine (oral administration) seven days before induction of epilepsy, followed by one day after epilepsy. TLE was induced by microinjection of kainite into the left lateral ventricle. The total mTOR and Drp1 levels in the hippocampus were evaluated by western blotting. MFN1 was assessed using immunohistochemistry, and the expression of Fis.1 and MTFP1 (fission-related proteins) and OPA (fusion-related protein) were detected by real-time PCR. The mitochondrial membrane potential was measured by Rhodamin 123. The results showed that 72 h after induction of epilepsy, the mTOR protein level increased, and the balance of the mitochondrial dynamic was disturbed; however, oral administration of NAC decreased the mTOR protein level and improved the mitochondrial dynamic. These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level, which can improve the imbalance in the mitochondrial dynamic.

Curcumin-coated gold nanoparticles attenuate doxorubicin-induced cardiotoxicity via regulating apoptosis in a mouse model.

Doxorubicin (DOX) is one of the most widely used chemotherapy agents; however, its nonselective effect causes cardiotoxicity. Curcumin (Cur), a well known dietary polyphenol, could exert a significant cardioprotective effect, but the biological application of this substance is limited by its chemical insolubility. To overcome this limitation, in this study, we synthesised gold nanoparticles based on Cur (Cur-AuNPs). Ultraviolet-visible (UV-Vis) absorbance spectroscopy and transmission electron microscopy (TEM) were performed for the characterisation of synthesised NPs, and Fourier transform infrared (FTIR) spectroscopy were applied to detect Cur on the surface of AuNPs. Its cytotoxicity effect on H9c2 cells was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The biological efficacy of Cur-AuNPs was assessed after acute cardiotoxicity induction in BALB/c mice with DOX injection. The serum biomarkers, myocardial histological changes, and cardiomyocyte apoptosis were then measured. The results revealed that the heart protection by Cur-AuNPs is more effective than Cur alone. Heart protective effect of Cur-AuNPs was evident both in the short-term (24 hours) and long-term (14 days) study. The results of Cur-AuNPs400 after 24 hours of toxicity induction displayed the reduction of the cardiac injury serum biomarkers (LDH, CK-MB, cTnI, ADT, and ALT) and apoptotic proteins (Bax and Caspase-3), as well as increase of Bcl-2 anti-apoptotic proteins without any sign of interfibrillar haemorrhage and intercellular spaces in the heart tissue microscopic images. Our long-term study signifies that Cur-AuNPs400 in DOX-intoxicated mice could successfully inhibit body and heart weight loss in comparison to DOX group.

GSK-3ß as a target for apigenin-induced neuroprotection against Aß 25-35 in a rat model of Alzheimer's disease.

Glycogen synthase kinase-3 (GSK-3) is a critical molecule in Alzheimer's disease (AD) that modulates two histopathological hallmarks of AD: Amyloid beta (Aß) plaques and neurofibrillary tangles composed of aberrant hyper-phosphorylation of tau protein. This study was performed to investigate the protective effect of flavone apigenin through inhibition of GSK-3 and the involvement of this kinase in the inhibition of BACE1 expression and hyperphosphorylation of tau protein in an AD rat model. 15 nM of aggregated amyloid-beta 25-35 was microinjected into the left lateral ventricle of an AD rat. Apigenin (50 mg/kg) was administered orally 45 min before the Aß injection and continued daily for three weeks. Immunohistochemistry and western blot analysis showed that apigenin significantly reduced the hyperphosphorylation of tau levels in the hippocampus. Real-time PCR analysis revealed significant inhibition of the mRNA level of ß secretase (BACE1) and GSK-3ß, but Apigenin had no effect on the level of GSK-3α. The results demonstrate that apigenin has a protective effect against amyloid-beta 25-35 by decreasing the expression of GSK-3ß with the consequence of lowering the hyperphosphorylation of tau protein and suppressing BACE1 expression.

Investigating the potential mechanisms of depression induced-by COVID-19 infection in patients.

The new coronavirus (COVID-19) has emerged now in the world as a pandemic. The SARS-CoV-2 infection causes variant common symptoms, such as dry cough, tiredness, dyspnea, fever, myalgia, chills, headache, chest pain, and conjunctivitis. Different organs may be affected by COVID-19, such as the respiratory system, gastrointestinal tract, kidneys, and CNS. However, the information about the COVID-19 infection in the CNS is insufficient. We do know that the virus can enter the central nervous system (CNS) via different routes, causing symptoms such as dizziness, headache, seizures, loss of consciousness, and depression. Depression is the most common disorder among all neurological symptoms following COVID-19 infection, although the mechanism of COVID-19-induced depression is not yet clear. The aim of the present study is to investigate the probable mechanisms of COVID-19-induced depression. The reasons for depression in infected patients may be due to social and pathological factors including social quarantine, economic problems, stress, changes in the HPA axis, inflammation due to the entry of proinflammatory cytokines into the CNS, production of inflammatory cytokines by microglia, mitochondrial disorders, damage to the hippocampus, and malnutrition. By evaluating different factors involved in COVID-19-induced depression, we have concluded that depression can be minimized by controlling stress, preventing the cytokine storm with appropriate anti-inflammatory drugs, and proper nutrition.

Mitochondrial ATP-sensitive potassium channel, MitoKATP, ameliorates mitochondrial dynamic disturbance induced by temporal lobe epilepsy.

Temporal lobe epilepsy leads to a disturbance in the function and dynamic of the mitochondria. The mitoKATP channel is an important factor in controlling mitochondrial function. In this study, the protective role of mitoKATP was studied in temporal lobe epilepsy through the regulation of mitochondrial dynamic proteins. After induction of epilepsy, 5-HD (the inhibitor of mitoKATP) was administered daily for either 24 or 72 h. The results revealed an imbalance in dynamic proteins after epilepsy, specifically in the first 72 h. The disturbance in the mitochondrial dynamic worsened after blocking mitoKATP. In conclusion, mitoKATP has an important role in balancing mitochondrial dynamic proteins in epilepsy.

How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms.

The new coronavirus has spread throughout the world in a very short time and now has become a pandemic. Most infected people have symptoms such as dry cough, dyspnea, tiredness, and fever. However, the Covid-19 infection disrupts various organs, including the liver, kidney, and nervous system. Common neurological symptoms of the Covid-19 infection include delirium, confusion, headache, and loss of sense of smell and taste. In rare cases it can cause stroke and epilepsy. The virus enters the nervous system either directly through nerve pathways or indirectly through the ACE2 receptor. The neurological symptoms of a Covid-19 infection in the brain are mainly due to either the entry of pro-inflammatory cytokines into the nervous system or the production of these cytokines by microglia and astrocytes. Pro-inflammatory cytokines can cause blood-brain barrier disruption, increase in glutamate and aspartate and reduce GABA levels, impairs the function of ion channels, and finally, high levels of cytokines can cause epilepsy. Understanding the potential mechanisms is necessary to gain better insight into COVID-19 induced seizure pathogenesis and to design the correct treatment strategies to achieve appropriate treatment for seizure and epilepsy.

The possible role of progranulin on anti-inflammatory effects of metformin in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent and drug-resistant form of parietal epilepsy. TLE is accompanied by neuroinflammation in the brain, which involves reactive glial cells. Metformin is an old antidiabetic drug with anti-inflammatory and neuroprotective effects. Considering the importance of inflammation in epilepsy, we have investigated the effect of metformin on astrogliosis markers as well as pro and anti-inflammatory cytokines and its effect on progranulin expression (an important neuroprotective protein in epilepsy) in a rat TLE model. TLE was induced by intracerebroventricular microinjection of kainic acid. Metformin was orally administered for two weeks before the induction of epilepsy. Astrogliosis markers (GFAP and S100B), as well as IL-1ß and IL- 10 levels, were detected by ELISA. The progranulin level was measured by Western blotting and immunohistochemistry in the hippocampus. Our results showed basal levels of GFAP, S100B, and pro-inflammatory cytokine increased in the epileptic rats but were significantly ameliorated after pretreatment with metformin. However, anti-inflammatory cytokine and progranulin also increased in the pre-treated rats and metformin alone group. An increment in the progranulin level emphasizes the importance of this protein in epilepsy. Hence, metformin may exert at least some of its anti-inflammatory effects by increasing progranulin level. In sum, we have concluded that progranulin can be a key mediator in epilepsy, and the anti-inflammatory action of metformin in status epilepticus is through increasing the secretion of IL-10 and inhibiting IL-1 ß and astrogliosis.

Evaluation of the ameliorative effects of oral administration of metformin on epileptogenesis in the temporal lobe epilepsy model in rats.

AIMS: Understanding the underlying molecular mechanisms involved in epileptogenesis is necessary to target the best therapeutic interventions in epilepsy. Recently, it has been postulated that metformin, an old antidiabetic oral drug, has anti-seizure properties mostly due to its antioxidant activities. This study was designed to evaluate the ameliorative effects of metformin on the progression of epilepsy in the temporal lobe epilepsy model in rats. MAIN METHODS: Temporal lobe Epilepsy was induced by intracerebroventricular microinjection of kainic acid. Metformin was orally administered for two weeks before induction of epilepsy. Anti-epileptogenic activity of metformin was evaluated by intracranial electroencepholography (IEEG) recording to detect spontaneous seizures, mossy fiber sprouting by Timm staining, neurogenesis by BrdU staining. KEY FINDINGS: Oral administration of metformin prior to kainite-induced status epilepticus blocked the variant characterizations of epileptogenesis like neuronal cell death, aberrant neurogenesis, mossy fiber sprouting, and spontaneous seizures. SIGNIFICANCE: These findings indicate that metformin has potential anti-epileptogenic properties in temporal lobe epilepsy.

Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats.

AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin. MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured. KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2). In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups. SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.

2-Deoxyglucose protects hippocampal neurons against kainate-induced temporal lobe epilepsy by modulating monocyte-derived macrophages (mo-MΦ) and progranulin production in the hippocampus.

Inflammation is an important factor in the pathology of epilepsy with the hallmarks of resident microglia activation and infiltration of circulating monocytes in the damaged area. In the case of recovery and tissue repair, some monocytes change to macrophages (mo-MΦ) to enhance tissue repair. 2-deoxyglucose (2DG) is an analog of glucose capable of protecting the brain, and progranulin is a neurotrophic factor produced mainly by microglia and has an inflammation modulator effect. This study attempted to evaluate if one of the neuroprotective mechanisms of 2-DG is comprised of increasing monocyte-derived macrophages (mo-MΦ) and progranulin production. Status epilepticus (SE) was induced by i.c.v. injection of kainic acid (KA).2DG (125/mg/kg/day) was administered intraperitoneally. Four days later, animals were sacrificed. Their brain sections were then stained with Cresyl violet and Fluoro-Jade B to count the number of necrotic and degenerating neurons in CA3 and Hilus of dentate gyrus of the hippocampus. Lastly, immunohistochemistry was used to detect CD11b + monocyte, macrophage cells, and Progranulin level was evaluated by Western blotting. The histological analysis showed that 2DG can reduce the number of necrotic and degenerating neurons in CA3 and Hilar areas. Following KA administration, a great number of cD11b+ cells with monocyte morphology were observed in the hippocampus. 2DG not only reduced cD11b+ monocyte cells but was able to convert them to cells with the morphology of macrophages (mo-MΦ). 2DG also caused a significant increase in progranulin level in the hippocampus. Because macrophages and microglia are the most important sources of progranulin, it appears that 2DG caused the derivation of monocytes to macrophages and these cells produced progranulin with a subsequent anti-inflammation effect. In summary, it was concluded that 2DG is neuroprotective and probably one of its neuroprotective mechanisms is by modulating monocyte-derived macrophages by progranulin production.

Trigonelline protects hippocampus against intracerebral Aß(1-40) as a model of Alzheimer's disease in the rat: insights into underlying mechanisms.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common phenotype of dementia. Trigonelline is an alkaloid found in medicinal plants such as fenugreek seeds and coffee beans with neuroprotective potential and according to existing evidences, a favorable agent for treatment of neurodegenerative disorders. In this study, the possible protective effect of trigonelline against intracerebral Aß(1-40) as a model of AD in the rat was investigated. For induction of AD, aggregated A(1-40) (10 µg/2 휇l for each side) was bilaterally microinjected into the hippocampal CA1 area. Trigonelline was administered p.o. at a dose of 100 mg/kg. The results showed that trigonelline pretreatment of Aß-microinjected rats significantly improves spatial recognition memory in Y maze and performance in novel object recognition (NOR) task, mitigates hippocampal malondialdehyde (MDA), protein carbonyl, lactate dehydrogenase (LDH), and improves mitochondrial membrane potential (MMP), glutathione (GSH), and superoxide dismutase (SOD) with no significant change of catalase activity, nitrite level, caspase 3 activity, and DNA fragmentation. Additionally, trigonelline ameliorated hippocampal levels of glial fibrillary acidic protein (GFAP), S100b, cyclooxygenase 2 (Cox2), tumor necrosis factor α (TNFα), and interleukin 6 (IL-6) with no significant alteration of inducible nitric oxide synthase (iNOS). In addition, trigonelline pretreatment prevented loss of hippocampal CA1 neurons in Aß-microinjected group. Therefore, our results suggest that trigonelline pretreatment in Aß model of AD could improve cognition and is capable to alleviate neuronal loss through suppressing oxidative stress, astrocyte activity, and inflammation and also through preservation of mitochondrial integrity.

Evaluation of the neuroprotective, anticonvulsant, and cognition-improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway.

OBJECTIVES: Cognitive deficit is a common problem in epilepsy. A major concern emergent from the use of antiepileptic drugs includes their side effects on learning and memory. Herbal medicine is considered a complementary and alternative therapy in epilepsy. Apigenin is a safe flavone with antioxidant properties. However, there is little information about the beneficial effect of apigenin on cognition in epilepsy. MATERIALS AND METHODS: For evaluating the anticonvulsant effect of apigenin in the kainite temporal epilepsy model, apigenin was orally administered at 50 mg/kg for six days. Reference and working memory were examined via the Morris water maze and Y-maze task spontaneously. RESULTS: Results showed that apigenin had significant anticonvulsant activity (P<0.01) and restored the memory-deficit induced by kainic acid (P<0.05). Furthermore, apigenin significantly increased the number of living neurons in the hilus (P<0.001). Immunohistochemical analysis showed that apigenin reduced the release of cytochrome c (P<0.01), suggesting an inhibitory role in the intrinsic apoptotic pathway. CONCLUSION: These results suggest that apigenin restores memory impairment via anticonvulsant and neuroprotective activity.

Protective Role of Apigenin Against Aß 25-35 Toxicity Via Inhibition of Mitochondrial Cytochrome c Release.

INTRODUCTION: Cognitive dysfunction is the most common problem of patients with Alzheimer Disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of Amyloid Beta (Aß) is one of the earliest pathological features of AD. The flavone apigenin has been reported to play some protective roles in AD through the anti-oxidative and anti-inflammatory properties. This study aimed at investigating the effects of apigenin on spatial working memory and neural protection by restoring mitochondrial dysfunction and inhibition of caspase 9. METHODS: Intracerebroventricular (ICV) microinjection of Aß 25-35 was used for AD modeling. Working memory was assessed 21 days later using the Y maze test. Neuronal loss was detected in the hilar area of the hippocampus using Nissl and Fluoro-jade B staining, whereas immunohistochemistry was used to illustrate cytochrome c positive cells and caspase 9. RESULTS: The results revealed that apigenin significantly ameliorated spatial working memory. It also significantly reduced the number of degenerative neurons in the hilus area. Apigenin almost completely blocked the release of cytochrome c and caspase 9 in hilus. CONCLUSION: Apigenin may improve the spatial working memory deficits and neuronal degeneration through the amelioration of the mitochondrial dysfunction.

The role of rosemary extract in degeneration of hippocampal neurons induced by kainic acid in the rat: A behavioral and histochemical approach.

Systemic Kainic Acid (KA) administration has been used to induce experimental temporal lobe epilepsy in rats. The aim of this study was to evaluate the neuroprotective effect of rosemary extract (RE, 40% Carnosic acid) against KA-induced neurotoxicity in hippocampus and impaired learning and memory. Animals received a single dose of KA (9.5 mg/kg) intraperitoneally (i.p.) (KA group) and were observed for 2 h and were scored from 0 (for normal, no convulsion) to 5 (for continuous generalized limbic seizures). RE (100 mg/kg, orally) was administered daily for 23 days, starting a week before KA injection (KA+RE group). Neuronal degeneration in hippocampus was demonstrated by using Fluoro-Jade B immunofluorescence. The number of pyramidal cells in hippocampus was evaluated by Nissl staining. Also, the Morris Water Maze and Shuttle box have been used to assess spatial memory and passive avoidance learning, respectively. Our results revealed that, after treatment with RE, neuronal loss in CA1 decreased significantly in the animals in KA+RE group. The Morris water navigation task results revealed that spatial memory impairment decreased in the animals in KA+RE group. Furthermore, results in Shuttle box test showed that passive avoidance learning impairment significantly, upgraded in the animals in KA+RE group. These results suggest that RE may improve the spatial and working memory deficits and also neuronal degeneration induced by toxicity of KA in the rat hippocampus, due to its antioxidant activities.

Riluzole ameliorates learning and memory deficits in Aß25-35-induced rat model of Alzheimer's disease and is independent of cholinoceptor activation.

Alzheimer's disease (AD) is a major global public health concern and social care problem that is associated with learning, memory, and cognitive deficits. Riluzole is a glutamate modulator which has shown to improve memory performance in aged rats and may be of benefit in Alzheimer's disease. In the present study, its beneficial effect on attenuation of learning and memory deficits in Aß25-35-induced rat model of AD was assessed. Riluzole administration at a dose of 10mg/kg/day p.o. improved spatial memory in Morris water maze and retention and recall in passive avoidance task and its protective effect was not neutralized following intracerebroventricular microinjection of muscarinic or nicotinic receptor antagonists. Further biochemical analysis showed that riluzole pretreatment of intrahippocampal Aß-microinjected rats is able to attenuate hippocampal AChE activity and lower some oxidative stress markers, i.e. MDA and nitrite, with no significant change of the defensive enzyme catalase. Furthermore, riluzole prevented hippocampal CA1 neuronal loss and reduced 3-nitrotyrosine immunoreactivity. It is concluded that riluzole could exert a protective effect against memory decline induced by intrahippocampal Aß25-35 through anti-oxidative, anti-cholinesterase, and neuroprotective potential and its beneficial effect is possibly independent of cholinoceptor activation.

Pelargonidin improves memory deficit in amyloid ß25-35 rat model of Alzheimer's disease by inhibition of glial activation, cholinesterase, and oxidative stress.

Alzheimer's disease (AD) is a multifactorial disorder with devastating outcomes and few mostly palliative available therapeutic strategies. Pelargonidin (Pel), an anthocyanin compound, is an estrogen receptor agonist with lower side effects versus estrogen. This study examined neuroprotective effect of Pel on intrahippocampal amyloid ß25-35 (Aß) rat model of AD. Rats were divided into groups of sham, Aß, and Pel-pretreated Aß (10mg/kg; p.o.). Animals underwent Morris water maze (MWM) test in addition to measurement of hippocampal oxidative stress, acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS). Pel pretreatment of Aß group significantly improved escape latency and distance swum in MWM versus Aß group and attenuated hippocampal malondialdehyde (MDA) and increased catalase activity with no significant change of nitrite. Meanwhile, Pel improved hippocampal AChE activity and lowered GFAP level with no significant change of iNOS. Our results suggest that Pel could improve Aß25-35-induced memory deficit through mitigation of oxidative stress, cholinergic dysfunction, and astrocyte reaction.

Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer's Disease Via Estrogen Receptor Independent Pathways.

Alzheimer's disease (AD) is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel), an anthocyanin derivative, is an estrogen receptor agonist with little estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aß) intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential estrogen receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aß intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O), α estrogen antagonist intra-cerebrovascular (i.c.v.) microinjected, and ß estrogen antagonist (i.c.v) microinjected animals. Intrahippocampal microinjections of Aß were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aß microinjections significantly improved step-through latency (P<0.001) in passive avoidance test. In α and ß estrogen, antagonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively) compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aß induced memory dysfunction in passive avoidance test performance through estrogen receptor independently related pathways.

Protection of Hippocampal CA1 Neurons Against Ischemia/Reperfusion Injury by Exercise Preconditioning via Modulation of Bax/Bcl-2 Ratio and Prevention of Caspase-3 Activation.

INTRODUCTION: Ischemia leads to loss of neurons by apoptosis in specific brain regions, especially in the hippocampus. The purpose of this study was investigating the effects of exercise preconditioning on expression of Bax, Bcl-2, and caspase-3 proteins in hippocampal CA1 neurons after induction of cerebral ischemia. METHODS: Male rats weighing 260-300 g were randomly allocated into three groups (sham, exercise, and ischemia). The rats in exercise group were trained to run on a treadmill 5 days a week for 4 weeks. Ischemia was induced by the occlusion of both common carotid arteries (CCAs) for 20 min. Levels of expression of Bax, Bcl-2, and caspase-3 proteins in CA1 area of hippocampus were determined by immunohistochemical staining . RESULTS: The number of active caspase-3-positive neurons in CA1 area were significantly increased in ischemia group, compared to sham-operated group (P<0.001), and exercise preconditioning significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P<0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in ischemia group, compared to sham-operated group (P<0.001). DISCUSSION: This study indicated that exercise has a neuroprotective effects against cerebral ischemia when used as preconditioning stimuli.