P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice

Memory impairment is the most common symptom in patients with Alzheimer’s disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition-enhancing potential.     

Z-Guggulsterone Improves the Scopolamine-Induced Memory Impairments Through Enhancement of the BDNF Signal in <Emphasis Type="Italic">C57BL</Emphasis>/<Emphasis Type="Italic">6J</Emphasis> Mice

Memory impairment is a common symptom in patients with neurodegenerative disorders, and its suppression could be beneficial to improve the quality of life of those patients. Z-guggulsterone, a compound extracted from the resin of plant Commiphora whighitii, exhibits numerous pharmacological effects in clinical practice, such as treatment of inflammation, arthritis, obesity and lipid metabolism disorders. However, the role and possible mechanism of Z-guggulsterone on brain-associated memory impairments are largely unknown. This issue was addressed in the present study in a memory impairment model induced by scopolamine, a muscarinic acetylcholine receptor antagonist, using the passive avoidance, Y-maze and Morris water maze tests. Results showed that scopolamine significantly decreased the step-through latency and spontaneous alternation of C57BL/6J mice in passive avoidance and Y-maze test, whereas increased the mean escape latency and decreased the swimming time in target quadrant in Morris water maze test. Pretreatment of mice with Z-guggulsterone at doses of 30 and 60 mg/kg effectively reversed the scopolamine-induced memory impairments. Mechanistic studies revealed that Z-guggulsterone pretreatment reversed the scopolamine-induced increase in acetylcholinesterase (AchE) activity, as well as decreases in brain-derived neurotrophic factor (BDNF) protein expression and cAMP response element-binding protein (CREB), extracellular regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) phosphorylation levels in the hippocampus and cortex. Inhibition of the BDNF signal, however, blocked the memory-enhancing effect of Z-guggulsterone. Therefore, these findings demonstrate that Z-guggulsterone attenuates the scopolamine-induced memory impairments mainly through activation of the CREB-BDNF signaling pathway, thereby exhibiting memory-improving effects.     

PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia-reperfusion injury: involvement of PI3K-Akt

Peroxisome proliferator-activated receptors (PPAR) regulate the expression of genes involved in lipid metabolism, energy production, and inflammation. Their role in ischaemia-reperfusion (I/R) is less clear, although research indicates involvement of PPARs in some forms of preconditioning. This study aimed to explore the effects of PPAR-α activation on the I/R injury and potential cardioprotective downstream mechanisms involved. Langendorff-perfused hearts of rats pretreated with the selective PPAR-α agonist WY-14643 (WY, pirinixic acid; 3 mg·(kg body mass)·day(-1); 5 days) were subjected to 30 min ischaemia - 2 h reperfusion with or without the phosphatidylinositol 3-kinase (PI3K)-Akt inhibitor wortmannin for the evaluation of functional (left ventricular developed pressure, LVDP) recovery, infarct size (IS), and reperfusion-induced arrhythmias. A 2-fold increase in baseline PPAR-α mRNA levels (qPCR) in the WY-treated group and higher post-I/R PPAR-α levels compared with those in untreated controls were accompanied by similar changes in the expression of PPAR-α target genes PDK4 and mCPT-1, regulating glucose and fatty acid metabolism, and by enhanced Akt phosphorylation. Post-ischaemic LVDP restoration in WY-treated hearts reached 60% ± 9% of the pre-ischaemic values compared with 24% ± 3% in the control hearts (P < 0.05), coupled with reduced IS and incidence of ventricular fibrillation that was blunted by wortmannin. Results indicate that PPAR-α up-regulation may confer preconditioning-like protection via metabolic effects. Downstream mechanisms of PPAR-α-mediated cardioprotection may involve PI3K-Akt activation.     

Effects of Scopolamine and Melatonin Cotreatment on Cognition,Neuronal Damage,and Neurogenesis in the Mouse Dentate Gyrus

It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.     

Chondroprotection of PPARα activation by WY14643 via autophagy involving Akt and ERK in LPS‐treated mouse chondrocytes and osteoarthritis model

Autophagy maintains cellular homoeostasis. The enhancement of autophagy in chondrocytes could prevent osteoarthritis (OA) progression in articular cartilage. Peroxisome proliferator‐activated receptor α (PPARα) activation may also protect articular chondrocytes against cartilage degradation in OA. However, whether the protective effect of activated PPARα is associated with autophagy induction in chondrocytes is not determined. In this study, we investigated the effect of PPARα activation by its agonist, WY14643, on the protein expression level of Aggrecan and ADAMTS5, and the protein expression level of autophagy biomarkers, including LC3B and P62, using Western blotting analysis in isolated mouse chondrocytes pre‐treated with lipopolysaccharides (LPS, mimicking OA chondrocytes) with or without the autophagy inhibitor chloroquine diphosphate salt. Furthermore, Akt and ERK phosphorylation was detected in LPS‐treated chondrocytes in response to WY14643. In addition, the effect of intra‐articularly injected WY14643 on articular cartilage in a mouse OA model established by the destabilization of the medial meniscus was assessed using the Osteoarthritis Research Society International (OARSI) histopathology assessment system, along with the detection of Aggrecan, ADAMTS5, LC3B and P62 protein levels using immunohistochemistry assay. The results indicated that PPARα activation by WY14643 promoted proteoglycan synthesis by autophagy enhancement in OA chondrocytes in vivo and in vitro concomitant with the elevation of Akt and ERK phosphorylation. Therefore, autophagy could contribute to the chondroprotection of PPARα activation by WY14643, with the implication that PPARα activation by WY14643 may be a potential approach for OA therapy.     

Daidzein activates choline acetyltransferase from MC-IXC cells and improves drug-induced amnesia

The choline acetyltransferase (ChAT) activator, which enhances cholinergic transmission via an augmentation of the enzymatic production of acetylcholine (ACh), is an important factor in the treatment of Alzheimer's disease (AD). Methanolic extracts from Pueraria thunbergiana exhibited an activation effect (46%) on ChAT in vitro. Via the sequential isolation of Pueraria thunbergiana, the active component was ultimately identified as daidzein (4',7-dihydroxy-isoflavone). In order to investigate the effects of daidzein from Pueraria thunbergiana on scopolamine-induced impairments of learning and memory, we conducted a series of in vivo tests. Administration of daidzein (4.5 mg/kg body weight) to mice was shown significantly to reverse scopolamine-induced amnesia, according to the results of a Y-maze test. Injections of scopolamine into mice resulted in impaired performance on Y-maze tests (a 37% decreases in alternation behavior). By way of contrast, mice treated with daidzein prior to the scopolamine injections were noticeably protected from this performance impairment (an approximately 12%-21% decrease in alternation behavior). These results indicate that daidzein might play a role in acetylcholine biosynthesis as a ChAT activator, and that it also ameliorates scopolamine-induced amnesia.     

Delayed neuroprotection against cerebral ischemia reperfusion injury: putative role of BDNF and GSK-3β

Aim: Numerous studies have demonstrated the possible neuroprotective role of lithium treatment against neurological disorders. However, the role of lithium in delayed phase of neuronal death against focal ischemia has not been explored. Therefore, the present study was designed to investigate the effect and molecular mechanisms of post-lithium treatment against cerebral ischemic reperfusion (I/R) injury and associated cognitive deficits in rats. Methods: I/R injury was induced by right middle cerebral artery occlusion and lithium (40 and 60?mg/kg) were given intraperitoneally, 24?h after the insult and continued for 1 week with 24-h interval. Using Lasser Doppler, cerebral blood flow was monitored before, during and after MCAO induction. Besides behavioral, biochemical, and histological evaluation, levels of tumor necrosis factor alpha (TNF-α) and brain-derived neurotrophic factor (BDNF) were also estimated. Results: I/R injury resulted in significant elevation of neurological deficits, oxidative stress, neuroinflammation, and cognitive impairments. We found that lithium injection, 24?h after I/R-injury continued for 1 week, dose dependently prevented behavioral abnormality and cognitive impairments. Moreover, lithium attenuated the levels of oxidative stress and pro-inflammatory-cytokines TNF-α level. Further, lithium treatments significantly reduced neuronal damage and augmented healthy neuronal count and improved neuronal density in hippocampus. These neuroprotective effects of delayed lithium treatment were associated with upregulation of neurotrophic factor BDNF levels. Conclusion: Delayed lithium treatment provides neuroprotection against cerebral I/R injury and associated cognitive deficits by upregulating BDNF expression that opens a new avenue to treat I/R injury even after active cell death.     

Estradiol treatment and its interaction with the cholinergic system: effects on cognitive function in healthy young women

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.     

ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, significantly improved scopolamine-induced memory impairment in mice

We assessed the effects of oral treatments of ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, on learning and memory deficit. The cognition-enhancing effect of ESP-102 was investigated in scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze performance tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with ESP-102 (doses in the range of 10 to 100 mg/kg body weight) significantly reduced scopolamine-induced memory deficits in the passive avoidance performance test. Another noteworthy result included the fact that prolonged oral daily treatments of mice with much lower amounts of ESP-102 (1 and 10 mg/kg body weight) for ten days reversed scopolamine-induced memory deficits. In the Morris water maze performance test, both acute and prolonged oral treatments with ESP-102 (single administration of 100 mg/kg body weight or prolonged daily administration of 1 and 10 mg/kg body weight for ten days, respectively, significantly ameliorated scopolamine-induced memory deficits as indicated by the formation of long-term and/or short-term spatial memory. In addition, we investigated the effects of ESP-102 on neurotoxicity induced by amyloid-beta peptide (Abeta25-35) or glutamate in primary cultured cortical neurons of rats. Pretreatment of cultures with ESP-102 (0.001, 0.01 and 0.1 mug/ml) significantly protected neurons from neurotoxicity induced by either glutamate or Abeta25-35. These results suggest that ESP-102 may have some protective characteristics against neuronal cell death and cognitive impairments often observed in Alzheimer's disease, stroke, ischemic injury and other neurodegenerative diseases.     

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.     

Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643

This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus. Transient cerebral ischemia (30 min), followed by 1-24 h reperfusion, significantly increased the generation of reactive oxygen species, nitric oxide (NO), and lipid peroxidation end-products, as well as markedly reducing levels of the endogenous antioxidant glutathione. Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). Pretreatment with WY14643 suppressed oxidative stress and expression of HO-1, iNOS, and ICAM-1, but had no effect on COX-2. These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB. The PPAR-alpha antagonist MK886 abolished the beneficial effects of WY14643. The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643. We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke.     

Peroxisome proliferator-activated receptor-α activation protects against endoplasmic reticulum stress-induced HepG2 cell apoptosis

Live ischemia–reperfusion injury is associated with endoplasmic reticulum (ER) stress-induced apoptosis. Activation of peroxisome proliferator-activated receptor-α (PPARα) may inhibit hepatocyte apoptosis induced by oxidative stress and protect against liver injury. This study aimed to investigate the effects of PPARα activation, through a specific agonist, on ER stress-induced apoptosis in human liver hepatocellular carcinoma (HepG2) cells. HepG2 cells were challenged with H₂O₂ and treated with WY14643, a selective PPARα agonist, in the presence or absence of the PPARα antagonist of MK886. Cell viable assay (MTT) and immunostaining were used to evaluate cell viability. The level of apoptotic cell death was quantified through Annexin V/PI staining. Alanine aminotransferase, asparatate aminotransferase, and malondialdehyde levels were measured to determine the presence of cellular injury and oxidative stress. RT-PCR and Western blot analysis were used to detect mRNA and protein expression of PPARα, BiP, and CHOP. Immunofluorescence was utilized to determine the intracellular localization of CHOP. H₂O₂ and MK886 both reduced the viability of HepG2 cells, increased oxidative stress and apoptosis, up-regulated the BiP and CHOP expression, and induced CHOP translocation from the cytoplasm to the nucleus. Compared with cells treated with H₂O₂ alone, pre-administration of WY14643 increased cell viability, attenuated apoptosis, improved cell function, down-regulated BiP and CHOP expression and inhibited CHOP translocation. The effects of WY14643 were completely abolished using the MK886 antagonist. PPARα activation protects against H₂O₂-induced HepG2 cell apoptosis. The underlying mechanisms may be associated with its activation to suppress excessive ER stress.     

Estradiol treatment and its interaction with the cholinergic system: Effects on cognitive function in healthy young women

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.     

Nodakenin, a coumarin compound, ameliorates scopolamine-induced memory disruption in mice

Nodakenin is a coumarin compound initially isolated from the roots of Angelica gigas. In the present study, we investigated the effects of nodakenin on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Nodakenin (10 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test and the Y-maze test (P<0.05), and also reduced escape latency during training in the Morris water maze test (P<0.05). Moreover, swimming times and distances within the target zone of the Morris water maze were greater in the nodakenin-treated group than in the scopolamine-treated group (P<0.05). In an in vitro study, nodakenin was found to inhibit acetylcholinesterase activity in a dose-dependent manner (IC(50)=84.7 microM). In addition, nodakenin was also found to inhibit acetylcholinesterase activity for 6 h in an ex-vivo study. These results suggest that nodakenin may be a useful for the treatment of cognitive impairment, and that its beneficial effects are mediated, in part, via the enhancement of cholinergic signaling.     

Galantamine reverses scopolamine-induced behavioral alterations in Dugesia tigrina

In planaria (Dugesia tigrina), scopolamine, a nonselective muscarinic receptor antagonist, induced distinct behaviors of attenuated motility and C-like hyperactivity. Planarian locomotor velocity (pLMV) displayed a dose-dependent negative correlation with scopolamine concentrations from 0.001 to 1.0 mM, and a further increase in scopolamine concentration to 2.25 mM did not further decrease pLMV. Planarian hyperactivity counts was dose-dependently increased following pretreatment with scopolamine concentrations from 0.001 to 0.5 mM and then decreased for scopolamine concentrations ≥1 mM. Planarian learning and memory investigated using classical Pavlovian conditioning experiments demonstrated that scopolamine (1 mM) negatively influenced associative learning indicated by a significant decrease in % positive behaviors from 86 % (control) to 14 % (1 mM scopolamine) and similarly altered memory retention, which is indicated by a decrease in % positive behaviors from 69 % (control) to 27 % (1 mM scopolamine). Galantamine demonstrated a complex behavior in planarian motility experiments since co-application of low concentrations of galantamine (0.001 and 0.01 mM) protected planaria against 1 mM scopolamine-induced motility impairments; however, pLMV was significantly decreased when planaria were tested in the presence of 0.1 mM galantamine alone. Effects of co-treatment of scopolamine and galantamine on memory retention in planaria via classical Pavlovian conditioning experiments showed that galantamine (0.01 mM) partially reversed scopolamine (1 mM)-induced memory deficits in planaria as the % positive behaviors increased from 27 to 63 %. The results demonstrate, for the first time in planaria, scopolamine’s effects in causing learning and memory impairments and galantamine’s ability in reversing scopolamine-induced memory impairments.     

Class I Histone Deacetylase Inhibitor Valproic Acid Reverses Cognitive Deficits in a Mouse Model of Septic Encephalopathy

Accumulating evidence suggests that histone deacetylase inhibitor exert neuroprotective effects in animal models of neurological diseases. We investigated for the first time whether class I histone deacetylase inhibitor valproic acid (VPA) can reverse cognitive deficits in a mouse model of sepsis-associated encephalopathy (SAE). Moreover, the possible mechanisms of protection were also explored. A mouse model of SAE was induced in adult male mice by cecal ligation and puncture (CLP). Mice received an administration of saline or VPA (100 mg/kg) once daily for 14 consecutive days starting either immediately or 2 weeks after operation. Furthermore, the TrkB antagonist K252a was used in another group of experiment to investigate whether brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway is involved in the protection of VPA. Our data suggested that CLP resulted in significant cognitive impairments accompanied by increased expressions in interleukin-1β and caspase-3, and decreased expressions in BDNF, phospho-TrkB (pTrkB), postsynaptic density 95, and synapses, which were reversed by VPA. However, TrkB antagonist K252a abolished the beneficial effects of VPA with regard to cognition and decreased pTrkB expression and synapses in the hippocampus. Taken together, the findings of the present study suggested chronic treatment with VPA reverses cognitive deficits through mechanisms probably via a reduction in inflammation and apoptosis in the brain, as well as the activation of the BDNF-TrkB signaling pathway in a mouse model of SAE.     

Cognition Enhancing and Neuromodulatory Propensity of <Emphasis Type="Italic">Bacopa monniera</Emphasis> Extract Against Scopolamine Induced Cognitive Impairments in Rat Hippocampus

Cognition-enhancing activity of Bacopa monniera extract (BME) was evaluated against scopolamine-induced amnesic rats by novel object recognition test (NOR), elevated plus maze (EPM) and Morris water maze (MWM) tests. Scopolamine (2 mg/kg body wt, i.p.) was used to induce amnesia in rats. Piracetam (200 mg/kg body wt, i.p.) was used as positive control. BME at three different dosages (i.e., 10, 20 and 40 mg/kg body wt.) improved the impairment induced by scopolamine by increasing the discrimination index of NOR and by decreasing the transfer latency of EPM and escape latency of MWM tests. Our results further elucidate that BME administration has normalized the neurotransmitters (acetylcholine, glutamate, 5-hydroxytryptamine, dopamine, 3,4 dihydroxyphenylacetic acid, norepinephrine) levels that were altered by scopolamine administration in hippocampus of rat brain. BME administration also ameliorated scopolamine effect by down-regulating AChE and up-regulating BDNF, muscarinic M1 receptor and CREB expression in brain hippocampus confirms the potent neuroprotective role and these results are in corroboration with the earlier in vitro studies. BME administration showed significant protection against scopolamine-induced toxicity by restoring the levels of antioxidant and lipid peroxidation. These results indicate that, cognition-enhancing and neuromodulatory propensity of BME is through modulating the expression of AChE, BDNF, MUS-1, CREB and also by altering the levels of neurotransmitters in hippocampus of rat brain.     

Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway

Convulsive status epilepticus (CSE) is a neurological disease with contraction and extension of limbs, leading to damage of hippocampus and cognition. This study aimed to explore the effects of dexmedetomidine (DEX) on the cognitive function and neuroinflammation in CSE rats. All rats were divided into control group, CSE group and DEX group. Morris water maze test was used to measure cognitive function. Acute hippocampal slices were made to detect long-term potentiation (LTP). Immunohistochemistry was used to determine the expression of α7-nicotinic acetylcholine receptor (α7-nAChR) and interleukin-1β (IL-1β). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of IL-1β, tumor necrosis factor-α (TNF-α), S-100β and brain-derived neurotrophic factor (BDNF). Our results showed that DEX improved the memory damage caused by CSE. DEX reduced seizure severity and increased the amplitudes and sustainable time of LTP, and also inhibited the hippocampal expression of α7-nAChR and IL-1β in CSE rats. DEX treatment decreased serum IL-1β, TNF-α and S-100β levels and increased BDNF levels. The effects of DEX on seizure severity and LTP could be simulated by nicotine or attenuated by concurrent α-bungarotoxin (α-BGT) treatment. In conclusions, DEX significantly improved spatial cognitive dysfunction, reduced seizure severity and increased LTP in CSE rats. Improvements by DEX were closely related to enhancement of cholinergic anti-inflammatory pathway.