Memory Deficits In Rats Research Articles

Sodium 4-Phenylbutyrate Protects Hypoxic-Ischemic Brain Injury via Attenuating Endoplasmic Reticulum Stress in Neonatal Rats.

Neonatal hypoxic-ischemic (HI) brain injury is associated with long-term neurological disorders, and protective strategies are presently scarce. Sodium 4-phenylbutyrate (4-PBA) reportedly acts as a chemical chaperone that alleviates endoplasmic reticulum (ER) stress, which plays a critical role in neurological diseases. The present study aimed to evaluate the neuroprotective effects of 4-PBA on HI-induced neonatal brain injury in a rat model, and to characterize possible underlying mechanisms. The HI brain injury model was established by ligating the left common carotid artery in 7-day-old rats, followed by exposure to 8% oxygen for 2 h. The 4-PBA or vehicle was administered by an intracerebroventricular injection 30 min before HI. The protein expression levels of ER stress markers (GRP78, ATF6, and CHOP) were detected by western blotting at 24 h after HI insult. The activation of cAMP-response element-binding protein (CREB) was evaluated by western blotting and immunofluorescence. TUNEL and Nissl staining were performed to detect the histomorphological changes in the hippocampal neurons at 24 h and 7 days, respectively, after HI injury. From days 29 to 34 after brain HI, rats underwent Morris water maze tests to assess cognitive functioning. The results showed that pretreatment with 4-PBA decreased HI-induced excessive ER stress and neuronal injury. Moreover, CREB activation might be involved in the beneficial effects of 4-PBA on HI-induced learning and memory deficits in rats. In conclusion, the present study suggested a potential therapeutic approach of ER stress inhibition in the treatment of neonatal HI brain injury.

Overexpression of protein kinase Mζ in the hippocampal dentate gyrus rescues amyloid-β-induced synaptic dysfunction within entorhinal-hippocampal circuit

Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (Aβ) impair synaptic transmission in experimental AD models. Protein kinase Mζ (PKMζ) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKMζ overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric Aβ 1-42 (oAβ) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 µL of lentiviral vector (~108 TU/mL) encoding PKMζ genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKMζ overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKMζ ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKMζ inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKMζ on synaptic activity and memory performance. PKMζ-dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD.

Protective effect of Prunus amygdalus nut extract on chronic unpredictable stress (CUS) induced memory deficits and biochemical alterations in rats

Stress intervenes in the brain’s capability to encode and regain information from a person, it alters the biochemical parameters in specific regions of the brain can cause long-term damage to various parts of brain. The present investigations aid in understanding the effect of the Prunus amygdalus nut extract on CUS induced memory deficits in rats. The methanolic extract with an antioxidant potential (~ 60%) and was selected for in vivo analysis. CUS was induced in rats using different stress paradigms for 10 days. On day 11 and 12, acquisition trials for memory evaluation were performed using Morris Water Maze. On day 13 and 10 days later on, i.e. day 23, short-term and long-term memory retrievals trials were evaluated, respectively. Treatment groups were given test methanolic extract an hour before the subjection of CUS. Biochemical estimations and histopathological studies were carried out using brain tissue homogenate and brain tissue section, respectively. CUS altered the Transfer Latency time in both acquisition and retrieval trials, indicating memory impairment, which was reduced significantly in extract-treated groups. Administration of P. amygdalus nut methanolic extract protected the rat brains against CUS-induced neuroinflammatory changes. The observed beneficial effects could be attributed to the antioxidant potential of P. amygdalus.

Neuroprotective Effect of 2-Aminoethoxydiphenyl Borate (2-APB) in Amyloid β-Induced Memory Dysfunction: A Mechanistic Study.

β-Amyloid (Aβ) peptide is a characteristic feature of Alzheimer's disease (AD) and accumulation of Aβ is associated with loss of synaptic plasticity and neuronal cell death. Aggregation of Aβ initiates numerous molecular signalling pathways leading to oxidative stress, mitochondrial dysfunction as well as an imbalance of calcium ion influx homeostasis. Recently, it has been shown that transient receptor potential melastatin 2 (TRPM2), a non-selective calcium-permeable cation channel has been postulated to play a vital role in the neuronal death, indicating the potential of TRPM2 inhibition in CNS disease. In this study, neuroprotective potential of 2-aminoethoxydiphenyl borate (2-APB), a broad-spectrum calcium channels blocker was investigated in Aβ-induced memory deficits in rats. In addition, effect of 2-APB on TRPM2 channels gene and protein expressions and also on calcium and memory related proteins was investigated in the hippocampus. Intracerebroventricular (I.C.V.) administration of Aβ (Aβ25-35, 10μg) markedly induced cognitive impairment and upregulation of mRNA and protein expression of TRPM2 in the hippocampus. In addition, AChE activity was also increased in the cortex of the Aβ administered animals. Three-week treatment with 2-APB led to the down-regulation of TRPM2 mRNA and protein expression in the hippocampus and also improved the cognitive functions which was evident from the behavioral parameters. Moreover, 2-APB treatment also increased the calcium and memory associated proteins namely p-CaMKII, p-GSK-3β, p-CREB and PSD-95 in the hippocampus and reduced the mRNA level of calcium buffering proteins and calcineurin A (PPP3CA) in the hippocampus. Furthermore, 2-APB treatment significantly reduced the AChE activity in the cortex. Thus, our findings suggest the neuroprotective effect of 2-APB in Aβ-induced cognitive impairment.

The neuroprotective effect of osthole against chronic sleep deprivation (CSD)-induced memory impairment in rats

AimSleep deprivation (SD) is a frequent health problem in modern society. Osthole (Ost), a natural coumarin, has antioxidant and neuroprotective properties. This study examined the functions of Ost in chronic sleep deprivation (CSD)-induced memory deficits in rats. Main methodsThe CSD rat model was constructed by applying Sleep Interruption Apparatus (SIA). The protective effect of Ost on memory ability of CSD rats was evaluated through behavioral tests. Modafinil (MOD) was a positive control for investigating the mechanisms underlying the actions of Ost. The oxidative stress changes in the cortex and hippocampus of the rats, histological changes in CA1 region in the hippocampus and the protein expressions of neural plasticity markers were measured. The hippocampal neurons were isolated from rats for evaluating the neuroprotective effects of Ost on glutamate-induced neuron injury in vitro. Key findingsOst administration significantly enhanced the cognitive performance of CSD rats in the open field test, object location recognition experiment, novel object recognition experiment, and Morris water maze test. Ost could effectively normalize the levels/activities of the antioxidant enzyme system in the cortex and hippocampus. Moreover, Ost administration reversed CSD-induced abnormal state of CA1 neurocytes and the down-regulated expressions of plasticity-related genes in vivo and in vitro. Additionally, Ost also notably up-regulated the expressions of Nrf2 and HO-1 previously down-regulated in CA1 neurocytes of CSD rats and in vitro. SignificanceOur findings showed that Ost alleviated CSD-induced cognitive deficits, and the activation of the Nrf2/HO-1 pathway might be involved in the neuroprotective action of Ost.

Effects of post-training administration of LY341495, as an mGluR2/3 antagonist on spatial memory deficit in rats fed with high-fat diet

High-fat diets (HFDs) adversely influence glutamate metabolism and neurotransmission. The precise role of the group II metabotropic glutamate receptors (mGluR2/3) antagonist on spatial memory deficit following consumption of HFD has not yet been clarified. Therefore, in this study, we examined the effects of post-training administration of mGluR2/3 antagonism; LY341495 on spatial memory in rats fed with HFD (for 10 weeks) by using Morris Water Maze (MWM) task. The training session for testing memory acquisition in MWM consisted of 4 trials per day for 4 consecutive days. Twenty-four hours after the last training session the spatial probe test (retention) was given. Intraperitoneal injection (i.p) injection of LY341495 was done 30min before probe test. Our results showed that 10 weeks consumption of HFD had no significant effect on escape latency and swimming distance in memory acquisition. Our finding showed that consumption of a HFD leads to reference memory impairment in the probe test. HFD animals spent less time in the target zone in compare with control animals. Also, LY341495 improved HFD-induced reference memory (retention) impairment. HFD animals treated with LY341495 spent more time in the target zone in compare with HFD animals. Escape latencies to find the visible platform during visual task were same in all experimental groups, indicating no visual impairment in the animals. We propose that a HFD may act through mGluR2/3 within the brain to reduce synaptic plasticity, which impairs memory retrieval, and post-training administration of LY341495 can reduce HFD-induced reference memory impairment.

WITHDRAWN: Resveratrol partially prevents learning and memory deficits in rats exposed to gaseous formaldehyde

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Blockage of ventrolateral periaqueductal gray matter cannabinoid 1 receptor increases dental pulp pain and pain-related subsequent learning and memory deficits in rats

Cannabinoid 1 receptor (CB1R) signaling has a pivotal role in the modulation of both pain and cognitive responses. This study aims at investigating the role of CB1R in the ventrolateral periaqueductal gray matter (vlPAG) on both pulpal pain and pain-related subsequent changes in learning and memory performances in rats. The adult male Wistar rats were cannulated in the vlPAG. The rats were pretreated by intra-vlPAG administration of selective CB1R antagonist AM-251 (2, 4 and 8 µg/rat) and vehicle dimethylsulfoxide. The drugs were microinjected 20 min before the induction of capsaicin-induced pulpalgia. The nociceptive behaviors were recorded for 40 min. Then, passive avoidance and spatial learning and memory were assessed using the shuttle box and Morris water maze tests, respectively. Following the administration of intradental capsaicin, there was a significant nociceptive response that increased after an induced blockage of CB1R by AM-251 at 4 and 8 µg. In addition, capsaicin impaired passive avoidance and spatial memory performance of rats. Microinjection of AM-251, prior to capsaicin, could dose-dependently exaggerate capsaicin-related learning and memory deficits in both tests. The present data indicated that the vlPAG endocannabinoid system is involved in the modulation of pain signals from dental pulp. It was also accompanied by learning and memory impairments.

A possible neuroprotective property of ethanol and/or NeuroAiD on the modulation of cognitive function

Cognitive impairments and poor performance on tasks needing behavioral flexibility are observable in chronic alcohol exposure. NeuroAid decreases cognitive deficits and improves functional outcomes by restoring neuronal circuits. The aim of the current study was to assess the hypothesis that ethanol exposure would induce neurobehavioral defects which may be reversed by the neuroprotective property of NeuroAid. Adult male Wistar rats were treated with saline, ethanol (0.2 g/kg), NeuroAid (0.8 g/kg) and ethanol (0.2 g/kg) + NeuroAid (0.8 g/kg). Then, behavioral tests were performed using the Y-maze apparatus, hot-plate and tail-flick apparatuses, locomotion apparatus as well as the loss of righting reflex (LORR) and hanging protocols (performance in a wire hanging test). Our results indicated that intraperitoneal (i.p.) administration of ethanol alone and administration of ethanol along with NeuroAid for one week reversed ethanol-induced spatial memory deficits in rats (P < 0.01). Interestingly, treatment with ethanol (0.2 g/kg) for one week induced nociception (P < 0.01). Moreover, one week administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) increased latency to LORR (P < 0.001) while four weeks administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) decreased sleep time (P < 0.01). In addition, a single administration of all drugs did not alter locomotor activity (P > 0.05) and hanging (P > 0.05). Improvement of behavioral tasks after one-week i.p. administration of ethanol and/or NeuroAid in comparison with a single administration of ethanol and/or NeuroAid may be due to the neuroprotective property of ethanol and/or NeuroAiD.

Genistein Prevents Single Prolonged Stress-Induced Cognitive Impairment in a Post-Traumatic Stress Disorder Rat Model via Activation of the Serotonergic System.

Post-traumatic stress disorder (PTSD) is a stress-associated mental disorder characterized by an imbalance of neurotransmitters in response to traumatic events or fear. Genistein (GEN), a natural isoflavone, has been shown to exhibit neuroprotective effects. Here, we used the Morris water maze (MWM) and object recognition task (ORT) tests to examine the effects of GEN on cognitive impairment in rats after exposure to single prolonged stress (SPS), and its interaction with the serotonergic system. After exposure to SPS, male rats received GEN (2, 4, and 10 mg/kg, i.p.) for 14 days. Daily GEN administration significantly improved cognitive function in the ORT and MWM tests. GEN treatment also inhibited SPS-induced decreases in serotonin (5-HT) levels in the medial prefrontal cortex and hippocampus. These increased 5-HT concentrations in response to GEN treatment could be partially attributed to the ratio of 5-hydroxyindoleacetic acid/5-HT in the hippocampus. Our findings suggest that GEN significantly attenuates SPS-induced memory deficits in rats and may represent an effective therapeutic option for the treatment of PTSD.

7,8-Dihydroxyflavone alleviated the high-fat diet and alcohol-induced memory impairment: behavioral, biochemical and molecular evidence.

Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12weeks in different experimental groups. 7,8-DHF (5mg/kg) was intraperitoneally injected daily for the last 4weeks (9th-12th week). The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.

Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients

Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, brain atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation is also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, is also linked to AD pathology. For example, bradykinin infusion into the hippocampus causes learning and memory deficits in rats, and blockade of the bradykinin receptor lessens cognitive impairment in AD mouse models. Even though it has been hypothesized that plasma bradykinin could contribute to inflammation in AD, the level of plasma bradykinin and its association with beta-amyloid (Aβ) pathology in AD patients had not been explored. Here, we assessed plasma bradykinin levels in AD patients and age-matched non-demented (ND) control individuals. We found significantly elevated plasma bradykinin levels in AD patients compared to ND subjects. Additionally, changes in plasma bradykinin levels were more profound in many AD patients with severe cognitive impairment, suggesting that peripheral bradykinin could play a role in dementia most likely via inflammation. Bradykinin levels in the cerebrospinal fluid (CSF) were reduced in AD patients and exhibited an inverse correlation with the CSF Aβ40/Aβ42 ratio. We also report that bradykinin interacts with the fibrillar form of Aβ and co-localizes with Aβ plaques in the post-mortem human AD brain. These findings connect the peripheral inflammatory pathway to cerebral abnormalities and identify a novel mechanism of inflammatory pathology in AD.

The effect of epigallocatechin-3-gallate on morphine-induced memory impairments in rat: EGCG effects on morphine neurotoxicity.

This investigation evaluated the capacity of epigallocatechin-3-gallate (EGCG) as the main polyphenolic compound in the green tea extract against memory impairment and neurotoxicity in morphine-treated rats. To measure the EGCG effect (5 and 50 mg/kg, i.p., co-treated with morphine) on spatial learning and memory of morphine-administrated male Wistar rats (45 mg/kg, s.c., 4 weeks), the Morris water maze test was used. Some apoptotic protein levels (Bax, Bcl-2, and cleaved caspase 3) were evaluated in the hippocampus tissue by the Western blot test. Also, oxidative stress status (malondialdehyde level, glutathione peroxidase, and superoxide dismutase activity) was measured in hippocampus tissue. The data presented that EGCG treatment (50 mg/kg) inhibited the morphine-induced memory deficits in rats. Also, EGCG administration reduced the apoptosis and oxidative stress in the hippocampus of morphine-treated rats. Our data indicate that EGCG can improve memory in morphine-treated rats. Molecular mechanisms underlying the detected effects could be related to the prevention of apoptosis and oxidative stress in the hippocampus of morphine-treated rats.

Neuroprotective effect of Reinwardtia indica against scopolamine induced memory-impairment in rat by attenuating oxidative stress.

Reinwardtia indica belongs to Linaceae family and used as a folk medicine in Asian countries. Traditionally, it has been used in the treatment of paralysis and anti-microbial in wound healing, etc. The current study was undertaken in order to investigate the antioxidant and memory protective effect of the alcoholic (99.90%) (AERI) and hydro-alcoholic (70:30) leaves extract (HAERI) of Reinwardtia indica, against scopolamine-induced memory impairment in animals and also tried to determine the possible mechanism of action. In addition, phytochemical profiling of alcoholic leaves extract was also conducted through gas chromatography-mass spectrometry (GC-MS/MS). Rats were pretreated with AERI, HAERI (dose 250 and 500mg/kg) and Donepezil (standard drug) along with scopolamine (1mg/kg) for a period of 14days followed by different test like elevated plus maze, passive avoidance, and Morris water maze to assess learning and memory ability. Acetylcholine levels, acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT & GSH), histopathology of the brain and biochemical test were also performed at the end of the treatment period. The scopolamine treatment resulted in learning and memory deficits which were partially and significantly ameliorated by the AERI at higher dose among other doses of extracts. The AERI at higher dose also counteracted the scopolamine-induced decrease in acetylcholine levels, increase in AChE activity, and decrease in antioxidant enzymes activities. No significant changes observed in the biochemical estimation of all dose of extracts. Histology of brain tissue showed the marked cellular changes in only scopolamine treated group while the standard, AERI and HAERI treated group were showing less damage at hippocampus region of the brain. The phytochemicals found after chemical profiling through GC-MS also supported the activity because of the presence of chemicals already reported for the neuroprotective, memory-enhancing and antioxidant activity, etc. The results demonstrated that the ability of the AERI at higher dose among all doses of extracts has more potential to revert the scopolamine-induced learning and memory deficits in rats by attenuating the decreased level of acetylcholine and antioxidant enzymes.

Neuroprotective Effect of Gallic Acid on Memory Deficit and Content of BDNF in Brain Entorhinal Cortex of Rat’s Offspring in Uteroplacental Insufficiency Model

Introduction: Uteroplacental insufficiency (UPI) causes neurodevelopmental deficits affecting the intrauterine growth restricted (IUGR) offspring. This study aimed to analyze the effects of Gallic acid (GA) on memory deficit and brain-derived neurotrophic factor (BDNF) content in entorhinal cortex of UPI rat models. Methods: In this experimental study, 40 pregnant Wistar rats were randomly divided into 5 groups, including: control, UPI, UPI+GA100, UPI+GA200and UPI+GA400. For IUGR induction, anterior uterine artery occlusion surgery was carried out on gestation day (GD) 18. From GD15, GA was administrated orally, in 100, 200 and 400 mg/kg BW doses until the birth of their neonates. Spatial and working memories are analyzed by Morris water maze and Y maze at postnatal day (PND) 30, respectively. Then, BDNF cerebral cortex level was estimated using ELISA technique.The data were analyzed through ANOVA and Tukey Post hoc in SPSS software version 16. Results: A significant decrease was observed in spatial and working memories and BDNF content in entorhinal cortex of UPI group in comparison with the control group (p˂0.05). On the other hand, GA-treated groups showed a significant increase in BDNF content and amelioration of spatial and working memories (p˂0.05). Conclusion: Fetal growth restrictionafter UPI by decreasingBDNFlevel in entorhinal cortex caused memory deficits in rat’s model. Moreover, neuroprotective effects of GA lead to increased BDNF content and ameliorate cognitive deficits in UPI model.

Co-treatment of vitamin D supplementation and aerobic training improves memory deficit in ovariectomized rat

Objective: Metabolic syndrome (MetS) and insufficient vitamin D levels are globally increasing phenomena which are correlated with cognitive impairment. This study investigated the interactive effect of aerobic training with vitamin D supplementation on memory deficit in rats with metabolic syndrome induced by ovariectomy.Methods: A total of forty Wistar rats weighing 240–255 gr were randomly matched on their body weight and divided into ovariectomy (OVX, n = 32) and sham-operated (SHAM; n = 8) groups. OV group was then divided into vitamin D supplementation (OVX + Vit D; 10000 IU/kg/week, for 8 weeks, n = 8), aerobic training (OVX + AT; n = 8), aerobic training and vitamin D supplementation (OVX + AT + Vit D; 10000 IU/kg/week, for 8 weeks, n = 8), and vehicle control group receiving sesame oil (OVX + Ses Oil; n = 8). After the end of intervention, passive avoidance learning and memory were assessed in step through passive avoidance paradigm. Obtained data were analyzed by ANOVA and post hoc Tukey test.Results: After 8 weeks of aerobic training and vitamin D supplementation, step through dark compartment latency (STL) was significantly higher and total time spent in that compartment (TSD) was lower in OVX + AT + Vit D compared to the other counterpart groups.Conclusion: Vitamin D supplementation combined with 8-week aerobic training alleviates cognitive impairment metabolic syndrome induced by ovariectomy.

Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling.

This study investigated the protective effect of Kaempferol against CdCl2-induced hippocampal damage and memory deficit in rats and investigated if such effects involve modulating the activity of AMPK/PTEN/Akt/mTOR axis. Adult male rats (n = 12/group) were divided into control or CdCl2-treated rats received the vehicle of Kaempferol for consecutive 6 weeks. Also, hippocampal cells were treated with CdCl2 in the presence or absence of Kaempferol for 24 h with or without 1 h pre-incubation with compound C, an AMPK inhibitor or with bpV a PTEN inhibitor. Kaempferol improved the behavioral of CdCl2-treated rats, preserved hippocampus structure and reduced hippocampal levels of ROS and protein levels of Bax and cleaved caspase-3. In both control and CdCl2-treated rats, Kaempferol significantly increased hippocampal levels of GSH levels and protein levels of Nfr2, Bcl2 and synaptic proteins (SNAP-25, PSD-25, and synapsin). Concomitantly, it increased the activity of PTEN and AMPK and subsequently, decreased the activity of Akt and mTOR. In cultured cells, individual pharmacological inhibition of PTEN by bpv or AMPK of compound C (CC) partially prevented the stimulatory effect of Kaempferol on Akt/mTOR and its inhibitory effect on cell death whereas a combination of both inhibitors completely prevented this. Also, inhibition of PTEN alone completely abolished the inhibitory effect of Kaempferol by synaptic proteins, whereas inhibition of AMPK completely abolished its stimulatory effect of Nfr2. In conclusion, Kaempferol protects against CdCl2-induced memory deficits and hippocampal apoptosis by its antioxidant potential and inhibition of Akt/mTOR axis and requires the activation of PTEN and AMPK.

Normalization of hippocampal retinoic acid level corrects age-related memory deficits in rats

Dietary micronutrients constitute a major environmental factor influencing aging processes. Vitamin A (vit. A) is the precursor of retinoic acid, a bioactive molecule that controls the expression of several genes involved in brain function. Evidence suggests a reduction of vit. A bioavailability with aging, but its impact on neuronal network is poorly understood. We investigated the mechanisms linking memory impairments with specific alterations of retinoic acid metabolism in the hippocampus. We compared young (10 weeks) and aged (16 months) rats, supplemented or not with dietary vit. A (20 IU retinol/g) for 4 weeks. Our study reveals that aging induced dysregulation of gene expression involved in vit. A and retinoic acid metabolism in the liver. Furthermore, vit. A supplementation restored the integrity of the hippocampal neuronal morphology altered by aging. Importantly, we found a high correlation between hippocampal levels of retinoic acid and memory performance. The present work establishes the link between collapse of retinoid metabolism and age-related cognitive decline, highlighting the role of vit. A in maintaining memory through aging.

TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models

Changes in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling are implicated in older people with dementia. Drugs that modulate the cAMP/cGMP levels in the brain might therefore provide new therapeutic options for the treatment of cognitive impairment in aging and elderly with dementia. Phosphodiesterase 2A (PDE2A), which is highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyze cAMP and cGMP. In this study, we investigated the effects of PDE2A inhibition on the cognitive functions associated with aging, such as spatial learning, episodic memory, and attention, in rats with a selective, brain penetrant PDE2A inhibitor, N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915). Repeated treatment with TAK-915 (3 mg/kg/day, p.o. for 4 days) significantly reduced escape latency in aged rats in the Morris water maze task compared to the vehicle treatment. In the novel object recognition task, TAK-915 (1, 3, and 10 mg/kg, p.o.) dose-dependently attenuated the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats. In addition, oral administration of TAK-915 at 10 mg/kg significantly improved the attentional performance in middle-aged, poorly performing rats in the 5-choice serial reaction time task. These findings suggest that PDE2A inhibition in the brain has the potential to ameliorate the age-related cognitive decline.

Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression of Small-Conductance Ca2+-Activated K+ Channels.

This study investigated the expression pattern, regulation of expression, and the role of hippocampal small-conductance Ca2+-activated K+ (SK) channels in memory deficits after cerebral hypoperfusion (CHP) with or without melatonin treatment, in rats. Adults male Wistar rats (n = 20/group) were divided into (1) a sham (2) a sham + melatonin (3) a two-vessel occlusion (2-VO) model, and (4) a 2-VO + melatonin. Melatonin was administered (i.p.)to all rats at a daily dose of 10mgkg-1 for 7days starting at the time of 2-VO-induction. In contrast to 2-VO rats, melatoninincreasedthe latencyofthe passive avoidance learning test and decreased time to find the hidden platform in Water Morris Test inall tested rats. In addition, it concomitantly downregulated SK1, SK2, and SK3 channels,downregulated mRNA levels of TNFα and IL-1β, enhanced BDNF levels and activity of PKA levels, and restored the levels ofcholinergicmarkersin the hippocampi of the treated-rats. Mechanistically, melatonin significantly prevented CHP-induced activation of ERK1/2, JNK, and P38 MAPKat least by inhibiting ROS generation and enhancing the total antioxidant potential. In cultured hypoxic hippocampal neurons, individual blockage of MAPK signaling by the MEK1/2 inhibitor (U0126), but not by the P38 inhibitor (SB203580) or JNK inhibitor (SP600125), completely prevented the upregulation of all three kinds of SK channels. These data clearly confirm that upregulation of SK channels plays a role in CHP-induced memory loss and indicate that melatonin reverses memory deficits after CHPin rats, at least by,downregulation of SK1, SK2, and SK3 channels in theirhippocampi.