Induced Memory Deficits Research Articles

The anti-epileptogenic and cognition enhancing effect of novel 1-[4-(4-benzo [1, 3] dioxol-5-ylmethyl-piperazin-1-yl)-phenyl]-3-phenyl-urea (BPPU) in pentylenetetrazole induced chronic rat model of epilepsy.

Epilepsy is a chronic neurological disorder which affects 65 million worldwide population and characterized by recurrent seizure in epileptic patients. Recently, we reported a novel piperonylpiperazine derivative, BPPU "1-[4-(4-benzo [1,3]dioxol-5-ylmethyl-piperazin-1-yl)- phenyl]-3-phenyl-urea'' as a potent anticonvulsant agent. BPPU has shown excellent anticonvulsant activity in various in-vivo seizure models along with good anti-depressant activity. In this report, we have deeply examined the anti-epileptogenic potential of BPPU in pentylenetetrazole (PTZ) induced kindling model and BPPU effectively reduced seizure episodes in kindled animals upto 35 days. Further, neuroprotective potential of BPPU against PTZ induced neurodegeneration has also been evaluated in hippocampus as well as cortex region by histopathological and immunohistochemical studies. Epileptic patients generally suffer from a range of cognitive impairments. Therefore, the cognition enhancing effect of BPPU was also measured by using well known social recognition test, novel object recognition test, light/dark test and open field test in kindled rat model as well as scopolamine induced memory deficit mice model. Results indicated that BPPU successfully improved cognition deficits in both models. Thus, BPPU appeared as a potent anti-epileptic agent which has also capability to improve cognition decline associated with epilepsy.

Inhibition of Histone Acetylation by ANP32A Induces Memory Deficits.

There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.

Imperatorin ameliorates lipopolysaccharide induced memory deficit by mitigating proinflammatory cytokines, oxidative stress and modulating brain-derived neurotropic factor

BackgroundLipopolysaccharide (LPS), an endotoxin from the outer membrane of Gram negative bacteria has been reported to cause neuroinflammation and learning and memory deficits. There are reports describing the beneficial effects of Imperatorin (IMP), a naturally occurring furanocoumarin in central nervous system (CNS) disorders such as anxiety and epilepsy. ObjectiveIn the current study, we investigated whether IMP protects against LPS mediated memory deficits and neuroinflammation. MethodsMice pretreated with IMP (5, 10 mg/kg po) were administered LPS (250 μg/kg ip) for 7 days. Memory was evaluated in the Morris water maze (MWM) and Y maze. The mice were euthanised and different biochemical assessments were carried out to measure oxidative stress and acetyl choline esterase (AChE). Further, evaluation of proinflammatory cytokines such as tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) levels and brain derived neurotrophic factor (BDNF) in hippocampus and cortex of brain were performed. ResultsLPS administration caused poor memory retention in both, MWM and Y maze, and caused distinct oxidative stress since decrease in superoxide dismutase (SOD), reduced glutathione (GSH) levels and increased lipid peroxidation were observed. Also, a significant rise was observed in the levels of AChE. Moreover, a rise in TNF-α and IL-6 levels and depleted levels of BDNF were noted. IMP pretreatment reversed LPS induced behavioral and memory disturbances and significantly decreased the oxidative stress and AChE levels. It also reduced TNF-α and IL-6 levels and caused a significant upregulation of BDNF levels. ConclusionPresent study highlights the potential neuroprotective role of IMP against LPS mediated cognitive impairment and neuroinflammation.

ONO-8590580, a Novel GABAAα5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models.

GABAA receptors containing α5 subunits (GABAAα5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAAα5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAAα5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAAα5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human α5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAα5 NAM activity for GABA-induced Cl- channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABAAα5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAAα5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice.

The analogous β-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer’s disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor α, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (γ-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases.

Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement.We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice.In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.

Sleep deprivation induced memory deficit are attributed to disrupted communications between amygdala and hippocampus

Sleep deprivation induced memory deficit are attributed to disrupted communications between amygdala and hippocampus

Role of Crataegus oxyacantha (Hawthorn) on scopolamine induced memory deficit and monoamine mediated behaviour in rats

Treatment of cognitive disorders is a challenging task in neurology since long time. Crataegus oxyacantha, also known as hawthorn belongs to family Rosaceae grown in colder areas and is one of the most widely used herb for the treatment of heart disorders. Traditionally Crataegus oxyacantha has also been used to treat Alzheimer disease, nervousness, stress, pain, and sleep disorders. In this study nootropic activity of petroleum ether, chloroform and methanol extract of Crataegus oxyacantha leaves was assessed using elevated plus maze model. Scopolamine (1 mg/kg) was used as amnesia inducing agent and piracetam (120 mg/kg) as standard nootropic drug. On the last day of the experiment, biochemical parameters like acetylcholinesterase, lipid peroxidase and superoxide dismutase were measured in brain homogenate. Effect of Crataegus oxyacantha on monoamines mediated behaviour was assessed through lithium induced head twitches and haloperidol induced catalepsy model in rats. Among all three extracts, methanol extract of Crataegus oxyacantha caused highest reduction in transfer latency time significantly as measured on 7th and 14th day and on 8th and 15th day on elevated maze and also decreased acetylcholinesterase and lipid peroxidase level and increased super oxide dismutase content as compared to scopolamine group. Methanol extract of Crataegus oxyacantha (200 mg/kg and 400 mg/kg) decreased number of head twitches and duration of catalepsy in rats significantly compared to vehicle treated group. So our study showed promising effect of Crataegus oxyacantha in enhancing learning and memory due to the presence of certain phytoconstituents.

20(S)-protopanaxadiol (PPD) alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of Egr-1, c-Fos and c-Jun in mice

20(S)-protopanaxadiol (PPD) possesses various biological properties, including anti-inflammatory, antitumor and anti-fatigue properties. Recent studies found that PPD functioned as a neurotrophic agent to ameliorate the sensory deficit caused by glutamate-induced excitotoxicity through its antioxidant effects and exhibited strong antidepressant-like effects in vivo. The objective of the present study was first to investigate the effect of PPD in scopolamine (SCOP)-induced memory deficit in mice and the potential mechanisms involved. In this study, mice were pretreated with PPD (20 and 40 μmol/kg) and donepezil (1.6 mg/kg) intraperitoneally (i.p) for 14 days. Then, open field test was used to assess the effect of PPD on the locomotor activity and mice were daily injected with SCOP (0.75 mg/kg) to induce cognitive deficits and then subjected to behavioral tests by object location recognition (OLR) experiment and Morris water maze (MWM) task. The cholinergic system function, oxidative stress biomarkers and protein expression of Egr-1, c-Fos, and c-Jun in mouse hippocampus were examined. PPD was found to significantly improve the performance of amnesia mice in OLR and MWM tests. PPD regulated cholinergic function by inhibiting SCOP-induced elevation of acetylcholinesterase (AChE) activity, decline of choline acetyltransferase (ChAT) activity and decrease of acetylcholine (Ach) level. PPD suppressed oxidative stress by increasing activities of antioxidant enzymes such as superoxide dismutase (SOD) and lowering maleic diadehyde (MDA) level. Additionally, PPD significantly elevated the expression of Egr-1, c-Fos, and c-Jun in hippocampus at protein level. Taken together, all these results suggested that 20(S)-protopanaxadiol (PPD) may be a candidate compound for the prevention against memory loss in some neurodegenerative diseases such as Alzheimer's disease (AD).

Mercurius solubilis attenuates scopolamine-induced memory deficits and enhances the motor coordination in mice

ABSTRACTAim: The present study was designed to investigate the effect of mercurius solubilis (merc sol) on scopolamine induced memory deficits and motor coordination in mice.Materials and methods: Three different formulations of merc sol (30X, 200M, 1M) were screened for their in vitro antioxidant potential through DPPH (2, 2-diphenyl-1-picrylhydrazyl) and nitric oxide scavenging activity using response surface methodology. Memory impairment was induced by the administration of scopolamine (1mg/kg i.p.) for 3 days to mice and assessment of memory acquisition and retention was done using Morris water maze test, passive avoidance test, elevated plus maze test, light and dark box test, motor coordination was evaluated using rotarod test and inclined plan test. The involvement of ion channels and nitric oxide pathway in the observed effect of merc sol was elucidated by administration of veratrine (0.125 μg/kg, i.p.), A23187 (20 μg/kg, i.p.), L- arginine (40 mg/kg, i.p.), aminoguanidine (50 mg/kg, i.p.) 30 min prior to merc sol. Acute toxicity studies were performed in accordance with the OECD (Organisation for Economic Co-operation and Development) guidelines.Results: In vitro studies have revealed merc sol 30 X to have maximum free radical and nitric oxide scavenging activity. Administration of merc sol 30 X to mice significantly reduced scopolamine induced memory deficits and motor incoordination in all the performance tasks. The calcium ionophore, A23187 significantly altered the effect of merc sol in mice. No major signs of toxicity were observed.Conclusion: Merc sol has antiamnesic effect in scopolamine induced deficits and motor coordination in mice.

The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats.

The involvement of histamine H3 receptors (H3Rs) in memory is well known, and the potential of H3R antagonists in therapeutic management of neuropsychiatric diseases, e.g., Alzheimer disease (AD) is well established. Therefore, the effects of histamine H3 receptor (H3R) antagonist E159 (2.5–10 mg/kg, i.p.) in adult male rats on dizocilpine (DIZ)-induced memory deficits were studied in passive avoidance paradigm (PAP) and in novel object recognition (NOR) using pitolisant (PIT) and donepezil (DOZ) as standard drugs. Upon acute systemic pretreatment of E159 at three different doses, namely 2.5, 5, and 10 mg/kg, i.p., 2.5 and 5 but not 10 mg/kg of E159 counteracted the DIZ (0.1 mg)-induced memory deficits, and this E159 (2.5 mg)-elicited memory-improving effects in DIZ-induced amnesic model were moderately abrogated after acute systemic administration of scopolamine (SCO), H2R antagonist zolantidine (ZOL), but not with H1R antagonist pyrilamine to the animals. Moreover, the observed memory-enhancing effects of E159 (2.5 mg/kg, i.p.) were strongly abrogated when animals were administered with a combination of SCO and ZOL. Furthermore, the E159 (2.5 mg)-provided significant memory-improving effect of in DIZ-induced short-term memory (STM) impairment in NOR was comparable to the DOZ-provided memory-enhancing effect, and was abolished when animals were injected with the CNS-penetrant histamine H3R agonist R-(α)-methylhistamine (RAMH). However, E159 at a dose of 2.5 mg/kg failed to exhibit procognitive effect on DIZ-induced long-term memory (LTM) in NOR. Furthermore, the results observed revealed that E159 (2.5 mg/kg) did not alter anxiety levels and locomotor activity of animals naive to elevated-plus maze (EPM), demonstrating that improved performances with E159 (2.5 mg/kg) in PAP or NOR are unrelated to changes in emotional responding or in spontaneous locomotor activity. These results provide evidence for the potential of drugs targeting H3Rs for the treatment of neuropsychiatric disorders, e.g., AD.

Lentivirus-mediated interleukin-1\u03b2 (IL-1\u03b2) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice

BackgroundRecent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1β may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1β in repairing behavioral changes by LPS remains unclear.MethodsThe mice were treated with either IL-1β shRNA lentivirus or non-silencing shRNA control (NS shRNA) lentivirus by microinjection into the dentate gyrus (DG) regions of the hippocampus. After 7 days of recovery, LPS (1 mg/kg, i.p.) or saline was administered. The behavioral task for memory deficits was conducted in mice by the novel object recognition test (NORT), the anxiety-like behaviors were evaluated by the elevated zero maze (EZM), and the depression-like behaviors were examined by the sucrose preference test (SPT) and the forced swimming test (FST). Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO1), IL-1β, tumor necrosis factor (TNF-α), neuropeptide VGF (non-acronymic), and brain-derived neurotrophic factor (BDNF) were assayed.ResultsOur results demonstrated that IL-1β knock-down in the hippocampus significantly attenuated the memory deficits and anxiety- and depression-like behaviors induced by LPS in mice. In addition, IL-1β knock-down ameliorated the oxidative and neuroinflammatory responses and abolished the downregulation of VGF and BDNF induced by LPS.ConclusionsCollectively, our findings suggest that IL-1β is necessary for the oxidative and neuroinflammatory responses produced by LPS and offers a novel drug target in the IL-1β/oxidative/neuroinflammatory/neurotrophic pathway for treating neuropsychiatric disorders that are closely associated with neuroinflammation, oxidative stress, and the downregulation of VGF and BDNF.

Fenugreek Seed Powder Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress, and Inflammation in a Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder that mainly affects the aged population and is characterized by the progressive loss of the hippocampal and cortical neurons, which results in memory and cognitive impairments. Trigonella foenum-graecum (fenugreek) has been reported to have hypoglycemic, hypocholesterolemic, hyperinsulinemic and anti-diabetic properties. Traditionally, it was used as a galactagogue and to treat anorexia, fever gastritis, gastric ulcers, and various nervous disorders. However, the neuroprotective effect of fenugreek seed powder against aluminum chloride (AlCl3) induced AD rats has not been analyzed. The result of the present study indicated that the chronic administration of AlCl3 induced significant learning and memory impairments, oxidative stress, and alterations in the protein immunocontent patterns of IDE and CDK5 (enzymes involved in the metabolism of tau and amyloid proteins), pTau, GFAP and Iba-1, IL-1β, IL-6, TNF-α, iNOS, NF-κB, COX-2, CDK5, BDNF, and STAT3. Our behavioral, biochemical, and molecular studies revealed that the co-administration of fenugreek seed powder significantly attenuated the AlCl3 induced memory deficits, amyloid and tau pathology, oxidative stress, and inflammation in AD rats could be due to the synergistic action of its active components.

Piracetam inhibits ethanol (EtOH)-induced memory deficit by mediating multiple pathways

Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown. In this study, we found that Pir inhibited ethanol-induced memory deficit by mediating multiple pathways. Treatment with EtOH could cause cognitive deficit in juvenile rats, and triggered the alteration of synaptic plasticity. Administration with Pir significantly increased long-term potentiation and protected hippocampus neurons from EtOH neurotoxicity. Pir intervention ameliorated EtOH-induced cell apoptosis and inhibited the activation of Caspase-3 in vitro, suggesting that Pir protected neurons by anti-apoptotic effects. Pir could decrease the expression of LC3-II and Beclin-1 induced by EtOH, and increase the phosphorylation of mTOR and reduce the phosphorylation of Akt, which suggested that the protective effect of Pir was involved in regulation of autophagic process and mTOR/Akt pathways. In conclusion, we speculate that Pir reduces EtOH-induced neuronal damage by regulation of apoptotic action and autophagic action, and our research offers preclinical evidence for the application of Pir in ethanol toxicity.

Exploration of multi-target potential of chromen-4-one based compounds in Alzheimer’s disease: Design, synthesis and biological evaluations

A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated for Acetylcholinesterase (AChE) inhibitory activity integrated with advanced glycation end products (AGEs) inhibitory and antioxidant potential. Most of the derivatives inhibited AChE in nanomolar IC50 range along with good AGEs inhibitory and radical scavenging activity. Among them, 7m, strongly inhibited AChE (IC50 = 5.87 nM) and found to be potent as compared to the reference drug donepezil (IC50 = 12.7 nM). Its potent inhibitory activity has been justified by docking analysis that revealed its dual binding characteristic with both CAS (catalytic active site) and PAS (peripheral anionic site) of AChE, simultaneously. Additionally, this compound also displayed ability to prevent advanced glycation end products formation (IC50 = 23.0 µM) with additional radical scavenging property (IC50 = 37.12 nM). It (7m) also ameliorated scopolamine induced memory deficit in mice employing Morris water maze test. Thus, flavonoids might be the promising lead compounds as potential polyfunctional anti-Alzheimer’s agents.

Mild traumatic brain injury induces memory deficits with alteration of gene expression profile

Repeated mild traumatic brain injury (rmTBI), the most common type of traumatic brain injuries, can result in neurological dysfunction and cognitive deficits. However, the molecular mechanisms and the long-term consequence of rmTBI remain elusive. In this study, we developed a modified rmTBI mouse model and found that rmTBI-induced transient neurological deficits and persistent impairments of spatial memory function. Furthermore, rmTBI mice had long-lasting detrimental effect on cognitive function, exhibiting memory deficits even 12 weeks after rmTBI. Microarray analysis of whole genome gene expression showed that rmTBI significantly altered the expression level of 87 genes which are involved in apoptosis, stress response, metabolism, and synaptic plasticity. The results indicate the potential mechanism underlying rmTBI-induced acute neurological deficits and its chronic effect on memory impairments. This study suggests that long-term monitoring and interventions for rmTBI individuals are essential for memory function recovery and reducing the risk of developing neurodegenerative diseases.

The protective effect of hydrogen sulfide (H2S) on traumatic brain injury (TBI) induced memory deficits in rats.

Traumatic brain injury (TBI), as an expanding public health epidemic, is a common cause of death among youth. TBI is associated with cognitive deficits and memory impairment. Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. In the present study the potential neuroprotective role of sodium hydrosulfide (NaHS), an H2S donor on TBI induced memory deficit in a rat model of controlled cortical impact (CCI) injury was investigated. CCI model was used to induce TBI. Male rats were randomly assigned into the following groups: control, sham, sham treated with NaHS, TBI, and TBI treated with NaHS (3 and 5mg/kg). NaHS was injected intraperitoneally 5min before TBI induction. Learning and memory were assessed using Morris water maze (MWM) on days 8-12 following injury. CCI resulted in MWM deficits. Injured animals showed a slower rate of acquisition with respect to the sham-operated animals [F (1, 24)=13.97, P<0.01, two-way ANOVA]. NaHS improved spatial memory impairment of injured rats. Treatment with NaHS (5 mg/kg) decreased the escape latency [F (1, 24)=7.559, P<0.05, two-way ANOVA] and traveled distance [F (1, 12)=6.398, P<0.05, Two way ANOVA)]. In probe test, injured animals spent less time in target zone (P<0.05, unpaired t-test) and NaHS did not have any effect on this parameter (p>0.05, one way ANOVA). These findings suggest that NaHS has a neuroprotective effect on TBI-induced memory impairment in rats.

Design, Synthesis and Molecular Docking Studies of New Potential Piperazine Derivatives as Cognition Enhancers.

In 2016, the statistical reports stated that Alzheimer is not just memory loss but it kills and has become the 6th leading cause of death. The number of dementia patients is increasing rapidly and expected to rise to 131.5 million by 2050. Still there is not a drug candidate that can cure the cognitive deficits completely. Series of novel piperazine derivatives have been designed, synthesized and evaluated for cognition enhancing activity. The synthesized compounds were screened for their in vitro AChE inhibition and reversal of scopolamine induced memory deficit in a passive avoidance stepdown animal model in mice. Enzyme kinetics and molecular docking studies were carried out to elucidate the mechanism of AChE inhibition. All the compounds exhibited excellent IC50 values with potential dual binding site inhibition activity. The IC50 values and inhibition constants of the most promising compounds 1d and 3c were found to be 2.23 μM, 1.05 μM, 14.38 μM and 6.93 μM respectively. They potentially reversed the scopolamine induced memory deficit at a dose of 1.0 mg/kg i.p. in mice. Furthermore, 1d and 3c showed high CNS penetration and brain AChE inhibition in ex vivo experiments. Additionally, significant free radical scavenging activity was determined taking trolox as the standard. Compounds 1d and 3c were emerged as promising of the series and further can be investigated for the future pursuit as drug candidates.

Neuroprotective effect of Indian propolis in β-amyloid induced memory deficit: Impact on behavioral and biochemical parameters in rats

The study aimed at the investigation of neuroprotective activity of macerated ethanolic extract of Indian propolis (MEEP) against β-Amyloid 25–35 (Aβ25-35) induced memory impairment in Alzheimer’s disease. MEEP was administrated orally to Wistar rats at doses of 100, 200 and 300mg/kg. Behavioral performances were evaluated using morris water maze and radial arm maze. At the end of behavioral study, the brains were removed and antioxidant parameters and brain monoamines were estimated. Further acetylcholinesterase (AchE) inhibition and brain-derived neurotropic factor (BDNF) were evaluated. In addition hematological parameters and histopathological tests were also carried out.In behavioral models, MEEP significantly (P<0.05) reversed the cognitive impairment of β amyloid-induced rats. The antioxidant potential was significantly increased (P<0.05) after administration of MEEP. Malondialdehyde levels were significantly (P<0.01) decreased in brain homogenate after treatment with MEEP extract as compared with diseased control group (group III). MEEP showed dose-dependent AChE inhibition and increased the levels of brain monoamines (P<0.05) as compared with group III. MEEP improved memory deficits by increasing BDNF in plasma (P<0.05).The study concludes that MEEP has anti-Alzheimer potential in rats through multiple mechanisms and further studies are ongoing for fractionation and biological screening.

PDE9 INHIBITION IMPROVES COGNITION IN MICE BY A MECHANISM DIFFERENT FROM THE ACETYLCHOLINE ESTERASE INHIBITOR DONEPEZIL

Phosphodiesterases (PDEs) in the brain have shown to play an important role in synaptic plasticity and cognitive function. Within this target class is PDE9, which specifically regulates the second messenger cGMP in neurons related to NMDA receptor signaling and is expressed in cognition relevant regions of the brain. Thus, PDE9 inhibitors are hypothesized to improve cognitive function via increasing NMDA receptor related cGMP signalling pathway to strengthen synaptic plasticity. This study characterizes the effect of a PDE9 inhibitor (compound A) on reversal of cognitively impaired mice in the T-maze task. In addition, brain cGMP levels were measured in these mice and correlated with memory performance in this task, and furthermore, compared with the effects of the acetylcholine esterase inhibitor donepezil. The molecular potency of compound A for PDE9 was determined using cytosolic extracts of SF9 insect cells over-expressing full-length human enzyme employing SPA technology. Regarding cognition, compound A was tested for reversal of MK-801 induced memory impairment in the mouse T-maze spontaneous alternation task after intraperitoneal administration. Subsequently, cGMP levels in mouse prefrontal cortex, hippocampus and striatum were measured by using enzyme immunoassay technique. The IC50 value of compound A on PDE9 was determined to be 88 nM. Regarding cognition, the PDE9 inhibitor could improve MK-801 induced memory deficits in the mouse T-maze task which was positively correlated with cGMP increase in prefrontal cortex, hippocampus and striatum, brain regions relevant for performance in this task. Donepezil also led to an improvement of memory deficits in the T-maze task, but this was not correlated with cGMP increase in brain. The study shows that compound A is a potent PDE9 inhibitor, and - corroborating previous reports on memory enhancing efficacy of other PDE9 inhibitors in rodents - it shows cognition enhancing efficacy in the mouse T-maze task. In contrast to donepezil, improvement of memory performance by PDE9 inhibition was correlated with a cGMP increase in cognitively relevant brain regions. Therefore, these data further demonstrate that PDE9 inhibition may be a potential approach to pharmacologically improve cognition in patients with Alzheimer's disease by a different mechanism compared to donepezil.