CSF amino acid profiles in ICV-streptozotocin-induced sporadic Alzheimer's disease in male Wistar rat: a metabolomics and systems biology perspective.

Alzheimer's disease (AD) is an increasingly important public health concern due to the increasing proportion of older individuals within the general population. The impairment of processes responsible for adequate brain energy supply primarily determines the early features of the aging process. Restricting brain energy supply results in brain hypometabolism prior to clinical symptoms and is anatomically and functionally associated with cognitive impairment. The present study investigated changes in metabolic profiles induced by intracerebroventricular-streptozotocin (ICV-STZ) in an AD-like animal model. To this end, male Wistar rats received a single injection of STZ (3 mg·kg-1) by ICV (2.5 µL into each ventricle for 5 min on each side). In the second week after receiving ICV-STZ, rats were tested for cognitive performance using the Morris Water Maze test and subsequently prepared for positron emission tomography (PET) to confirm AD-like symptoms. Tandem Mass Spectrometry (MS/MS) analysis was used to detect amino acid changes in cerebrospinal fluid (CFS) samples. Our metabolomics study revealed a reduction in the concentrations of various amino acids (alanine, arginine, aspartic acid, glutamic acid, glycine, isoleucine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and valine) in CSF of ICV-STZ-treated animals as compared to controls rats. The results of the current study indicate amino acid levels could potentially be considered targets of nutritional and/or pharmacological interventions to interfere with AD progression.

Kolaviron neuroprotective effect against okadaic acid-provoked cognitive impairment.

Alzheimer's disease (AD) is acknowledged as the main causative factor of dementia that affects millions of people around the world and is increasing at increasing pace. Okadaic acid (OA) is a toxic compound with ability to inhibit protein phosphatases and to induce tau protein hyperphosphorylation and Alzheimer's-like phenotype. Kolaviron (KV) is a bioflavonoid derived from Garcinia kola seeds with anti-antioxidative and anti-inflammation properties. The main goal of this study was to assess whether kolaviron can exert neuroprotective effect against okadaic acid-induced cognitive deficit. Rats had an intracerebroventricular (ICV) injection of OA and pretreated with KV at 50 or 100 mg/kg and examined for cognition besides histological and biochemical factors. OA group treated with KV at 100 mg/kg had less memory deficit in passive avoidance and novel object discrimination (NOD) tasks besides lower hippocampal levels of caspases 1 and 3, tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) as inflammatory factors, reactive oxygen species (ROS), protein carbonyl, malondialdehyde (MDA), and phosphorylated tau (p-tau) and higher level of acetylcholinesterase (AChE) activity, mitochondrial integrity index, superoxide dismutase (SOD), and glutathione (GSH). Moreover, KV pretreatment at 100 mg/kg attenuated hippocampal CA1 neuronal loss and glial fibrillary acidic protein (GFAP) reactivity as a factor of astrogliosis. In summary, KV was able to attenuate cognitive fall subsequent to ICV OA which is partly mediated through its neuroprotective potential linked to mitigation of tau hyperphosphorylation, apoptosis, pyroptosis, neuroinflammation, and oxidative stress and also improvement of mitochondrial health.

Pre- and post-treatment of α-Tocopherol on cognitive, synaptic plasticity, and mitochondrial disorders of the hippocampus in icv-streptozotocin-induced sporadic Alzheimer's-like disease in male Wistar rat.

Objective: Most dementia cases in the elderly are caused by Alzheimer's disease (AD), a complex, progressive neurological disease. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rat's results in aberrant brain insulin signaling, oxidative stress, and mitochondrial dysfunction that impair cognition change neural plasticity, and eventually lead to neuronal death. The current study aims to define the neuroprotective action of alpha-tocopherol in enhancing mitochondrial function and the function of synapses in memory-impaired rats brought on by icv-STZ. Methods: Male Wistar rats were pre-treated with (α-Tocopherol 150 mg/kg) orally once daily for 7 days before and 14 days after being bilaterally injected with icv-STZ (3 mg/kg), while sham group rats received the same volume of STZ solvent. After 2 weeks of icv-STZ infusion, rats were tested for cognitive performance using a behaviors test and then were prepared electrophysiology recordings or sacrificed for biochemical and histopathological assays. Results: The cognitive impairment was significantly minimized in the behavioral paradigms for those who had taken α-Tocopherol. In the hippocampus of icv-STZ rat brains, α-Tocopherol ocopherol effectively prevented the loss of glutathione levels and superoxide dismutase enzyme activity, lowered mitochondrial ROS and mitochondrial membrane potential, and also brought about a decrease in Aß aggregation and neuronal death. Conclusion: Our findings demonstrated that by lowering neurobehavioral impairments caused by icv-STZ, oxidative stress, and mitochondrial dysfunction, α-Tocopherol enhanced intracellular calcium homeostasis and corrected neurodegenerative defects in the brain. These findings examine the available approach for delaying AD connected to mitochondrial malfunction and plasticity issues.

Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets' insulin secretion induced by high-fat diet in rats.

Endoplasmic reticulum (ER) stress is involved in the development of glucose homeostasis impairment. When ER stress occurs, the unfolded protein response (UPR) is activated to cope with it. One of the UPR components is WFS1 (Wolfram syndrome 1), which plays important roles in ER homeostasis and pancreatic islets glucose-stimulated insulin secretion (GSIS). Accordingly and considering that feeding high-fat food has a major contribution in metabolic disorders, this study aimed to investigate the possible involvement of pancreatic ER stress in glucose metabolism impairment induced by feeding high-fat diet (HFD) in male rats. After weaning, the rats were divided into six groups, and fed on normal diet and HFD for 20 weeks, then 4-phenyl butyric acid (4-PBA, an ER stress inhibitor) was administered. Subsequently, in all groups, after performing glucose tolerance test, the animals were dissected and their pancreases were removed to extract ER, islets isolation and assessment of GSIS. Moreover, the pancreatic ER stress [binding of immunoglobulin protein (BIP) and enhancer-binding protein homologous protein (CHOP)] and oxidative stress [malondialdehyde (MDA), glutathione (GSH) and catalase] biomarkers as well as WFS1 expression level were evaluated. HFD decreased pancreatic WFS1 protein and GSH levels, and enhanced pancreatic catalase activity, MDA content, BIP and CHOP protein and mRNA levels as well as Wfs1 mRNA amount. Accordingly, it increased BIP, CHOP and WFS1 protein levels in the extracted ER of pancreas. In addition, the HFD caused glucose intolerance, and decreased the islets' GSIS and insulin content. However, 4-PBA administration restored the alterations. It seems that, HFD consumption through inducing pancreatic ER stress, altered WFS1 expression levels, reduced the islets' GSIS and insulin content and finally impaired glucose homeostasis.

Preliminary report of Iranian Registry of Alzheimer's disease in Tehran province: A cross-sectional study in Iran.

Background and Aims: Alzheimer's disease (AD) is the main cause of dementia and over the 55 million people live with dementia worldwide. We aimed to establish the first database called the Iranian Alzheimer's Disease Registry to create a powerful source for future research in the country. In this report, the design and early results of the Iranian Alzheimer's Disease Registry will be described. Methods: We performed this multicenter investigation and patients' data including age, sex, educational level, disease status, Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS) from 2018 to 2021 were collected, registered, and analyzed by GraphPad Prism software. Results: Totally 200 AD patients were registered in our database. 107 (54%) were women and age of 147 (74%) were over 65. The mean age for men and women was 76.20 ± 8.29 and 76.40 ± 8.83 years, respectively. 132 (66%) were married and 64 (32%) were illiterate. Also, 94 (47%) were in the moderate stage of disease, and 150 (75%) lived at home together with their families. The most frequent neurological comorbidity was psychosis (n = 72, 36%), while hypertension was the most common non-neurological comorbidity (n = 104, 52%). The GDS score of women in the mild stage (5.23 ± 2.9 vs. 6.9 ± 2.6, p = 0.005) and moderate stage (5.36 ± 2.4 vs. 8.21 ± 2.06, p = <0.001) of the disease was significantly greater than men. In univariate analysis, MMSC score was remarkably associated with stroke (ß = -2.25, p = 0.03), psychosis (ß = -2.18, p = 0.009), diabetes (ß = 3.6, p = <0.001), and hypercholesteremia (ß = 1.67, p = 0.05). Also, the MMSE score showed a notable relationship with stroke (ß = -2.13, p = 0.05) and diabetes (ß = 3.26, p = <0.001) in multivariate analysis. Conclusion: Iranian Alzheimer's Disease Registry can provide epidemiological and clinical data to use for purposes such as enhancing the current AD management in clinical centers, filling the gaps in preventative care, and establishing effective monitoring and cure for the disease.

The Effect of 40-Hz White LED Therapy on Structure-Function of Brain Mitochondrial ATP-Sensitive Ca-Activated Large-Conductance Potassium Channel in Amyloid Beta Toxicity.

Photobiomodulation therapy has become the focus of medical research in many areas such as Alzheimer's disease (AD), because of its modulatory effect on cellular processes through light energy absorption via photoreceptors/chromophores located in the mitochondria. However, there are still many questions around the underlying mechanisms. This study was carried out to unravel whether the function-structure of ATP-sensitive mitoBKCa channels, as crucial components for maintenance of mitochondrial homeostasis, can be altered subsequent to light therapy in AD. Induction of Aß neurotoxicity in male Wistar rats was done by intracerebroventricular injection of Aß1-42. After a week, light-treated rats were exposed to 40-Hz white light LEDs, 15 min for 7 days. Electrophysiological properties of mitoBKCa channel were investigated using a channel incorporated into the bilayer lipid membrane, and mitoBKCa-ß2 subunit expression was determined using western blot analysis in Aß-induced toxicity and light-treated rats. Our results describe that conductance and open probability (Po) of mitoBKCa channel decreased significantly and was accompanied by a Po curve rightward shift in mitochondrial preparation in Aß-induced toxicity rats. We also showed a significant reduction in expression of mitoBKCa-ß2 subunit, which is partly responsible for a leftward shift in BKCa Po curve in low calcium status. Interestingly, we provided evidence of a significant improvement in channel conductance and Po after light therapy. We also found that light therapy improved mitoBKCa-ß2 subunit expression, increasing it close to saline group. The current study explains a light therapy improvement in brain mitoBKCa channel function in the Aß-induced neurotoxicity rat model, an effect that can be linked to increased expression of ß2 subunit.

The effects of a chalcone derivative on memory, hippocampal corticosterone and BDNF levels in adult rats.

Purpose/Aim of the study: Since chalcones belong to the flavonoid family, the effects of a new synthetic chalcone derivative on memory, chronic stress, and expression of hippocampal BDNF gene were studied.Materials and methods: In this experiment, the male wistar rats were placed under restraint stress (6 h/day) for 21 days and then treated with a newly synthesized chalcone, containing methoxy on the aromatic rings or vehicles (20 mg/kg, intraperitoneal, IP). After the behavioral Passive avoidance, Open field, and Morris water maze tests, the levels of serum corticosterone (CORT) and hippocampal brain-derived neurotrophic factor (BDNF) were analyzed.Results: Results of these tests presented significant differences between the Stress (St) and Chalcone (Ch) groups. Chronic stress led to high CORT levels and impaired memory functions. Moreover, a single dose of synthetic chalcone in the St group could postpone memory impairments. Furthermore, a 20 mg/kg IP injection of chalcone markedly attenuated the decrease of hippocampal BDNF.Conclusions: It has been already proposed that flavonoids have beneficial effects on different types of memory. According to these results, further investigations are required to explore other factors besides BDNF that could be acutely modulated by chalcones.

Maternal stress induced endoplasmic reticulum stress and impaired pancreatic islets' insulin secretion via glucocorticoid receptor upregulation in adult male rat offspring.

Exposure to perinatal (prenatal and/or postnatal) stress is considered as a risk factor for metabolic disorders in later life. Accordingly, this study aimed to investigate the perinatal stress effects on the pancreatic endoplasmic reticulum (ER) stress induction, insulin secretion impairment and WFS1 (wolframin ER transmembrane Glycoprotein, which is involved in ER homeostasis and insulin secretion) expression changes, in rat offspring. According to the dams' period of exposure to variable stress, their male offspring were divided into, control (CTRL); pre-pregnancy, pregnancy, lactation stress (PPPLS); pre-pregnancy stress (PPS); pregnancy stress (PS); lactation stress (LS); pre-pregnancy, pregnancy stress (PPPS); pregnancy, lactation stress (PLS); pre-pregnancy, lactation stress (PPLS) groups. Offspring pancreases were removed for ER extraction and the assessment of ER stress biomarkers, WFS1 gene DNA methylation, and isolated islets' insulin secretion. Glucose tolerance was also tested. In the stressed groups, maternal stress significantly increased plasma corticosterone levels. In PPS, PS, and PPPS groups, maternal stress increased Bip (Hsp70; heat shock protein family A member 4), Chop (Ddit3; DNA- damage inducible transcript3), and WFS1 protein levels in pancreatic extracted ER. Moreover, the islets' insulin secretion and content along with glucose tolerance were impaired in these groups. In PPS, PS, LS and PPPS groups, the pancreatic glucocorticoid receptor (GR) expression increased. Maternal stress did not affect pancreatic WFS1 DNA methylation. Thus, maternal stress, during prenatal period, impaired the islets' insulin secretion and glucose homeostasis in adult male offspring, possibly through the induction of ER stress and GR expression in the pancreas, in this regard the role of WFS1 protein alteration in pancreatic ER should also be considered.

Paeonol exerts neuroprotective and anticonvulsant effects in intrahippocampal kainate model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is presented the most common form of focal epilepsy with involvement of oxidative stress and neuroinflammation as important factors in its development. About one third of epileptic patients are intractable to currently available medications. Paeonol isolated from some herbs with traditional and medicinal uses has shown anti-oxidative and anti-inflammatory effects in different models of neurological disorders. In this research, we tried to evaluate the possible protective effect of paeonol in intrahippocampal kainate murine model of TLE. To induce TLE, kainate was microinjected into CA3 area of the hippocampus and paeonol was administered at two doses of 30 or 50 mg/kg. The results of this study showed that paeonol at the higher dose significantly reduces incidence of status epilepticus, hippocampal aberrant mossy fiber sprouting and also preserves neuronal density. Beneficial protective effect of paeonol was in parallel with partial reversal of some hippocampal oxidative stress markers (reactive oxygen species and malondialdehyde), caspase 1, glial fibrillary acidic protein, heme oxygenase 1, DNA fragmentation, and inflammation-associated factors (nuclear factor-kappa B, toll-like receptor 4, and tumor necrosis factor α). Our obtained data indicated anticonvulsant and neuroprotective effects of paeonol which is somewhat attributed to its anti-oxidative and anti-inflammation properties besides its attenuation of apoptosis, pyroptosis, and astrocyte activity.

Effects of prenatal exposure to inflammation coupled with prepubertal stress on prefrontal white matter structure and related molecules in adult mouse offspring.

Maternal immune activation (MIA) by inflammatory agents such as lipopolysaccharide (LPS) and prepubertal stress (PS) may individually and collectively affect the central nervous system (CNS) during adulthood. Here, we intended to assess the effects of MIA, alone or combined with PS, on prefrontal white matter structure and its related molecules in adult mice offspring. Pregnant mice received either an i.p. dose of LPS (50 µg/kg) on gestational day 17 (GD17) or normal saline. Their pups were exposed to stress from postnatal days (PD) 30 to PD38 or no stress during prepubertal development. We randomly chose 56-day-old male offspring (n = 2 offspring per mother) from each group and isolated their prefrontal areas according to relevant protocols. The tissue samples were prepared for structural, histological, and molecular examinations. The LPS + stress group had evidence of increased damage in the white matter structures compared to the control, stress, and LPS groups (p < 0.05). The LPS + stress group also had significant downregulation of the genes involved in white matter formation (Sox10, Olig1, myelin regulatory factor, and Wnt compared with the control, stress, and LPS groups (p < 0.05). In conclusion, although each manipulation individually resulted in small changes in myelination, their combined effects were more pronounced. These changes were parallel to abnormal expression levels of the molecular factors that contribute to myelination.

The 40-Hz White Light-Emitting Diode (LED) Improves the Structure-Function of the Brain Mitochondrial KATP Channel and Respiratory Chain Activities in Amyloid Beta Toxicity.

It has been described that using noninvasive exposure to 40-Hz white light LED reduces amyloid-beta, a peptide thought to initiate neurotoxic events in Alzheimer's disease (AD). However, the mechanisms remain to be identified. Since AD impairs mitochondrial potassium channels and respiratory chain activity, the objectives of the current study were to determine the effect of 40-Hz white light LED on structure-function of mitoKATP channel and brain mitochondrial respiratory chain activity, production of reactive oxygen species (ROS), and ΔΨm in AD. Single mitoKATP channel was considered using a channel incorporated into the bilayer lipid membrane and expression of mitoKATP-Kir6.1 subunit as a pore-forming subunit of the channel was determined using a western blot analysis in Aß1-42 toxicity and light-treated rats. Our results indicated a severe decrease in mito-KATP channel permeation and Kir6.1 subunit expression coming from the Aß1-42-induced neurotoxicity. Furthermore, we found that Aß1-42-induced neurotoxicity decreased activities of complexes I and IV and increased ROS production and ΔΨm. Surprisingly, light therapy increased channel permeation and mitoKATP-Kir6.1 subunit expression. Noninvasive 40-Hz white light LED treatment also increased activities of complexes I and IV and decreased ROS production and ΔΨm up to ~ 70%. Here, we report that brain mito-KATP channel and respiratory chain are, at least in part, novel targets of 40-Hz white light LED therapy in AD.

Intranasal insulin improves the structure-function of the brain mitochondrial ATP-sensitive Ca2+ activated potassium channel and respiratory chain activities under diabetic conditions.

Although it is well established that diabetes impairs mitochondrial respiratory chain activity, little is known of the effects of intranasal insulin (INI) on the mitochondrial respiratory chain and structure-function of mitoBKCa channel in diabetes. We have investigated this mechanism in an STZ-induced early type 2 diabetic model. Single ATP-sensitive mitoBKCa channel activity was considered in diabetic and INI-treated rats using a channel incorporated into the bilayer lipid membrane. Because mitoBKCa channels have been involved in mitochondrial respiratory chain activity, a study was undertaken to investigate whether the NADH, complexes I and IV, mitochondrial ROS production, and ΔΨm are altered in an early diabetic model. In this work, we provide evidence for a significant decrease in channel open probability and conductance in diabetic rats. Evidence has been shown that BKCa channel ß2 subunits induce a left shift in the BKCa channel voltage dependent curve in low Ca2+ conditions,; our results indicated a significant decrease in mitoBKCa ß2 subunits using Western blot analysis. Importantly, INI treatment improved mitoBKCa channel behaviors and ß2 subunits expression up to ~70%. We found that early diabetes decreased activities of complex I and IV and increased NADH, ROS production, and ΔΨm. Surprisingly, INI modified the mitochondrial respiratory chain, ROS production, and ΔΨm up to ~70%. Our results thus demonstrate an INI improvement in respiratory chain activity and ROS production in brain mitochondrial preparations coming from the STZ early diabetic rat model, an effect potentially linked to INI improvement in mitoBKCa channel activity and channel ß2 subunit expression.

Hepatocyte Growth Factor Attenuates the Severity of Status Epilepticus in Kainic Acid-induced Model of Temporal Lobe Epilepsy by Targeting Apoptosis and Astrogliosis.

Introduction: Although pharmacotherapy is the most common treatment for epilepsy, proper seizure control is not achieved with current medications. This study evaluated the protective effects of the Hepatocyte Growth Factor (HGF) in a rat model of Temporal Lobe Epilepsy (TLE) and explored possible molecular mechanisms. Methods: A TLE rat model was determined using an intra-hippocampal kainic acid injection (4 µg). Intra-cerebrovascular injection of HGF (6 µg) was performed 30 min before kainic acid injection. Learning and memory impairment were investigated by behavioral tests. The Enzyme-Linked Immunosorbent (ELISA) was used to determine astrogliosis and DNA fragmentation. Changes in neuronal density and mossy fiber sprouting were evaluated by Nissl and Timm staining, respectively. Results: Behavioral assessments indicated that kainate-treated rats presented spontaneous seizures. Moreover, their alternation percentage scores in the Y-Maze test were lower (P<0.001). Likewise, the passive avoidance test confirmed learning disability in Kainate-treated rats (P<0.001). HGF administration reduced the number of spontaneous seizures, alternation percentage score (P<0.001), and cognitive disturbances (P<0.001). The histopathological results also showed that a protected HGF administration contributed to the reduction of neuronal loss in the CA3 subregion of the hippocampus and inhibited the formation of aberrant Mossy Fiber Sprouting (MFS) (P<0.01). Furthermore, the ELISA data indicated a significant decrease in GFAP (P<0.01) and DNA fragmentation (P<0.05) following HGF administration. Conclusion: Our findings demonstrated the validity of HGF in protection against the progression of the kainate-induced TLE in rats. This measure improved learning, cognitive disturbances and inhibited apoptosis and astrogliosis. Highlights: Temporal lobe epilepsy results in apoptosis of neuronal cells;Hepatocyte growth factor attenuates the severity of status epilepticus in kainic acid-induced model;Hepatocyte growth factor attenuates apoptosis of neuronal cells in kainic acid-induced model of temporal lobe epilepsy. Plain Language Summary: Epilepsy is known as a disorder of the CNS which is caused by an imbalance in the electrical activity of neurons that in turn results in derangement in cognitive or causing debilitating seizures. Hepatocyte growth factor is one of neurotrophins secreted from mesenchymal and epithelial cells that regulate the growth, survival and functional changes of cells through signaling pathways such as the tyrosine kinase pathway after binding to its specific receptor. In this study, we tried to find out the effect of hepatocyte growth factor on attenuation of the severity of status epilepticus in kainic acid-induced model of temporal lobe epilepsy. Our results show that hepatocyte growth factor is able to protect against progression of the kainate-induced temporal lobe epilepsy in rats by improvement of learning, cognitive disturbances and inhibiting of apoptosis and astrogliosis.

Ellagic acid ameliorates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis: Involvement of NLRP3 and pyroptosis.

Multiple sclerosis (MS) is presented as the most common autoimmune and demyelinating neurological disorder with incapacitating complications and with no definite therapy. Most treatments for MS mainly focus on attenuation of its severity and recurrence. To model MS reliably to study pathogenesis and efficacy of possible chemicals, experimental autoimmune encephalomyelitis (EAE) condition is induced in rodents. Ellagic acid is a neuroprotective polyphenol that can protect against demyelination. This study was planned and conducted to assess its possible beneficial effect in MOG-induced EAE model of MS with emphasis on uncovering its modes of action. Ellagic acid was given p.o. (at doses of 10 or 50 mg/kg/day) after development of clinical signs of MS to C57BL/6 mice immunized with MOG35-55. Results showed that ellagic acid can ameliorate severity of the disease and partially restore tissue level of TNFα, IL-6, IL-17A and IL-10. Besides, ellagic acid lowered tissue levels of NLRP3 and caspase 1 in addition to its mitigation of neuroinflammation, demyelination and axonal damage in spinal cord specimens of EAE group. As well, ellagic acid treatment prevented reduction of MBP and decreased GFAP and Iba1 immunoreactivity. Taken together, ellagic acid can decrease severity of EAE via amelioration of astrogliosis, astrocyte activation, demyelination, neuroinflammation and axonal damage that is partly related to its effects on NLRP3 inflammasome and pyroptotic pathway.

Neuroprotective and anticonvulsant effects of sinomenine in kainate rat model of temporal lobe epilepsy: Involvement of oxidative stress, inflammation and pyroptosis.

Oxidative stress, inflammation and pyroptosis are three of the most important mechanisms in the pathophysiology of temporal lobe epilepsy (TLE). Most people with TLE are refractory to the existing drugs. Sinomenine has shown neuroprotective effects through counteracting oxidative stress, inflammation and pyroptosis. In this study, we evaluated the effect of sinomenine on seizure behavior, oxidative stress, inflammation and pyroptosis markers in addition to its neuroprotective potential in intrahippocampal kainate-induced rat model of TLE. For this purpose, male rats (n = 60) were randomly divided into five groups, i.e., sham, kainate (lesion) with an intrahippocampal injection of kainate, kainate groups receiving sinomenine at doses of 30 or 50 mg/kg, and kainate group receiving valproic acid at a dose of 200 mg/kg (as the positive control). Our obtained data showed that sinomenine administration at a dose of 50 mg/kg can significantly decreases severity of seizures and incidence of status epilepticus (SE), hippocampal aberrant MFS and DNA fragmentation and prevents reduction of neuronal density. It also significantly restored level of ROS, MDA, HO-1 and SOD but its effect on GSH level was not significant. Additionally, sinomenine at a dose of 50 mg/kg partially counteracted the increase of NF-κB, TLR 4, TNFα, GFAP and caspase 1. These results suggest that sinomenine has anticonvulsant and neuroprotective effects by reducing hippocampal oxidative stress, inflammation, pyroptosis and apoptosis in intrahippocampal kainate model of TLE.

A new brain mitochondrial sodium-sensitive potassium channel: effect of sodium ions on respiratory chain activity.

We have determined the electropharmacological properties of a new potassium channel from brain mitochondrial membrane using a planar lipid bilayer method. Our results show the presence of a channel with a conductance of 150 pS at potentials between 0 and -60 mV in 200 mM cis/50 mM trans KCl solutions. The channel was voltage independent, with an open probability value of approximately 0.6 at different voltages. ATP did not affect current amplitude or open probability at positive and negative voltages. Notably, adding iberiotoxin, charybdotoxin, lidocaine or margatoxin had no effect on the channel behavior. Similarly, no changes were observed by decreasing the cis pH to 6. Interestingly, the channel was inhibited by adding sodium in a dose-dependent manner. Our results also indicated a significant increase in mitochondrial complex IV activity and membrane potential and a decrease in complex I activity and mitochondrial ROS production in the presence of sodium ions. We propose that inhibition of mitochondrial potassium transport by sodium ions on potassium channel opening could be important for cell protection and ATP synthesis.

The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson's disease model.

Loss of dopaminergic neurons following Parkinson's disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the protective effects of simultaneous inhibition of dipeptidyl peptidase-4 (DPP-4) and P2X7 purinoceptors in a PD model and explore possible mechanisms. The 6-hydroxydopamine (6-OHDA) was used as a tool to establish PD model in male Wister rats. The expressions of SIRT1, SIRT3, mTOR, PGC-1α, PTEN, P53 and DNA fragmentation were evaluated by ELISA assay. Behavioral impairments were determined using apomorphine-induced rotational and narrow beam tests. Dopamine synthesis and TH-positive neurons were detected by tyrosine hydroxylase (TH) immunohistochemistry. Neuronal density was determined by Nissl staining. OHDA-lesioned rats exhibited behavioral impairments that reversed by BBG, lin and lin + BBG. We found significant reduced levels of SIRT1, SIRT3, PGC-1α and mTOR in both mid brain and striatum from OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Likewise, significant increased levels of PTEN and P53 were found in both mid brain and striatum from OHDA-lesioned rats that was reversed by BBG, lin and lin + BBG. TH-positive neurons and neuronal density were markedly reduced OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Collectively, our results showed protective effects of simultaneous inhibition of DPP-4 and P2X7 purinoceptors in a rat model of PD can be linked to targeting SIRT1/SIRT3, PTEN-mTOR pathways. Moreover, our findings demonstrated that simultaneous inhibition of DPP-4 and P2X7 purinoceptors might have stronger effect on mitochondrial biogenesis compared to only one.

Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.

INTRODUCTION: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aß1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD. METHODS: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aß-lesioned groups. For modeling AD, aggregated Aß1-40 (10 µg/2 µl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway. RESULTS: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aß-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters. CONCLUSION: Findings of this study clearly demonstrated that microinjection of Aß1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.

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.