Prevents Memory Deficits Research Articles

Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1β); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1β, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Green tea protects against memory deficits related to maternal deprivation

Maternal deprivation (MD) in early life affects the development of the brain, causing cognitive losses in adulthood. Oxidative imbalance may be one of the factors that trigger these deficits. Therapies with antioxidant components, like green tea from Camellia sinensis (GT) has been used to treat or prevent memory deficits in a variety of conditions related to oxidative stress. Here we demonstrate that memory deficits caused by MD can be prevented by GT antioxidant activity in hippocampus. Pregnant female rats were used. Her puppies were submitted to MD and intake of GT. Recognition and aversive memory were evaluated, as well as hippocampal oxidative status. Data showed that MD prejudice short and long-term recognition and aversive memory and that GT protected memory. Hippocampal reactive oxygen species levels were increased in MD rats; this increase was avoided by GT supplementation. GSH was decreased on hippocampus MD rats. GT did not avoid GSH decrease, but promote the increase of total antioxidant capacity in MD rats' hippocampus. In conclusion, GT protects against memory deficits related to MD, and one of the implicated mechanism seems to be the antioxidant effects of GT.

Fluoxetine administration during adolescence attenuates cognitive and synaptic deficits in adult 3×TgAD mice

Fluoxetine (FLX) has broad neurobiological functions and neuroprotective effects; however, the preventive effects of FLX on cognitive impairments in Alzheimer's disease (AD) have not been reported. Here, we studied whether adolescent administration of fluoxetine can prevent memory deficits in AD transgenic mice that harbour PS1m146v, APPswe and TauP301L mutations (3 × TgAD). FLX was applied through peritoneal injection to the mice at postnatal day 35 (p35) for 15 consecutive days, and the effects of FLX were observed at 6-month. We found that adolescent administration of FLX improved learning and memory abilities in 6-month-old 3 × TgAD mice. FLX exposure also increased the sizes of the hippocampal CA1, dentate gyrus (DG) and extensive cortex regions, with increased numbers of neurons and higher dendritic spine density. Meanwhile, the synaptic plasticity of neurons in the hippocampus was remodelled, and the expression levels of synaptic-related proteins were increased along with activation of the cyclic AMP response element-binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signalling pathway. Finally, we found that FLX effectively prevented the increase of beta-amyloid (Aβ) levels. These data suggest that adolescent administration of the antidepressant drug FLX can efficiently preserve cognitive functions and improve pathologies in 3×Tg AD mice.

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

Oral sinensetin, but not nobiletin alone, prevents MK801‐induced impairment of memory formation in mice, like nobiletin‐rich chinpi, a kampo medicine

ABSTRACTAimOur pilot clinical study suggested that nobiletin‐rich Citrus reticulata peel, also known as nchinpi, has the potential to be beneficial as a kampo medicine for Alzheimer's disease. The nchinpi extract has a high content of polymethoxyflavones, including nobiletin and sinensetin. Our previous pharmacological study using cultured hippocampal neurons showed that the nchinpi extract more potently facilitated cAMP‐response element (CRE)‐mediated transcription associated with long‐term memory formation than did nobiletin alone, via a mechanism in which nobiletin and four other polymethoxyflavones, one being sinensetin, a potently CRE‐mediated transcription‐facilitating substance, cooperated. It remained unclear, however, whether nchinpi could be more effective in vivo in preventing memory deficits than could nobiletin alone. Here, we compared the impacts of the respective samples on N‐methyl‐D‐aspartate receptor antagonism‐induced learning and memory disability.MethodsThe nchinpi extract or nobiletin was orally given to mice for 7 consecutive days to examine their respective impacts on this impairment on contextual fear conditioning test. In a separate analysis, sinensetin's impact was evaluated.ResultsNchinpi extract at a dose corresponding to that of 25 mg/kg/day nobiletin prevented impaired memory formation, whereas nobiletin failed to exhibit such beneficial effects even when given at 50 mg/kg/day. Oral sinensetin prevented memory deficits at 25 mg/kg/day, unlike nobiletin.ConclusionNchinpi acting in a multicomponent drug‐like fashion in vitro has an obvious advantage over nobiletin alone in the ability to prevent memory dysfunction in animals as well and, hence, might be beneficial in patients with dementia.

Supplementation with different teas from Camellia sinensis prevents memory deficits and hippocampus oxidative stress in ischemia-reperfusion

Memory and cognition impairments resultant of ischemic stroke could be minimized or avoided by antioxidant supplementation. In this regard, the neuroprotective potential of Green tea from Camellia sinensis has been investigated. However, there is a lack of information regarding the neuroprotective potential of others teas processed from the Camellia sinensis. Here we investigate the neuroprotective role of green, red, white and black tea on memory deficits and brain oxidative stress in a model of ischemic stroke in rats. Our findings show that green and red teas prevent deficits in object and social recognition memories, but only green tea protects against deficits in spatial memory and avoids hippocampal oxidative status and intense necrosis and others alterations in the brain tissue. In summary, green tea shows better neuroprotection in ischemic stroke than the others teas from Camellia sinensis.

The p75 neurotrophin receptor regulates cranial irradiation-induced hippocampus-dependent cognitive dysfunction.

Cognitive deficits, characterized by progressive problems with hippocampus-dependent learning, memory and spatial processing, are the most serious complication of cranial irradiation. However, the underlying mechanisms remain obscure. The p75 neurotrophin receptor (p75NTR) is involved in a diverse arrays of cellular responses, including neurite outgrowth, neurogenesis, and negative regulation of spine density, which are associated with various neurological disorders. In this study, male Sprague-Dawley (SD) rats received 10 Gy cranial irradiation. Then, we evaluated the expression of p75NTR in the hippocampus after cranial irradiation and explored its potential role in radiation-induced synaptic dysfunction and memory deficits. We found that the expression of p75NTR was significantly increased in the irradiated rat hippocampus. Knockdown of p75NTR by intrahippocampal infusion of AAV8-shp75 ameliorated dendritic spine abnormalities, and restored synapse-related protein levels, thus preventing memory deficits, likely through normalization the phosphor-AKT activity. Moreover, viral-mediated overexpression of p75NTR in the normal hippocampus reproduced learning and memory deficits. Overall, this study demonstrates that p75NTR is an important mediator of irradiation-induced cognitive deficits by regulating dendritic development and synapse structure.

HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation.

Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4-24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6-24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory.SIGNIFICANCE STATEMENT The current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases.

Rutin protects against neuronal damage in vitro and ameliorates doxorubicin-induced memory deficits in vivo in Wistar rats.

Doxorubicin (DOX) is the most widely used broad-spectrum anticancer agent, either alone or in combination, for most cancers including breast cancer. Long-term use of chemotherapeutic agents to treat breast cancer patients results in cognitive complications with a negative impact on survivors’ quality of life. The study objective was to evaluate rutin (RUT) for its neuroprotective effect against DOX in human neuroblastoma (IMR32) cells in vitro and study its potential to ameliorate DOX-induced cognitive dysfunction in Wistar rats. Cell viability assay (3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neurite growth assay, detection of apoptosis by (acridine orange/ethidium bromide) staining, intracellular reactive oxygen species (ROS) assay, and flowcytometric analysis were carried out to assess neuroprotective potential against DOX. An in vivo study was conducted for assessing protective effect of RUT against memory deficit associated with DOX-induced chemobrain using object recognition task (ORT). Locomotion was assessed using open field test. Serum biochemistry, acetylcholinesterase, oxidative stress markers in hippocampus, and frontal cortex were assessed. Histopathological analysis of major organ systems was also carried out. Prior exposure to RUT at 100 µM protected IMR32 cells from DOX (1 µM) neurotoxicity. DOX exposure resulted in increased cellular death, apoptosis, and intracellular ROS generation with inhibition of neurite growth in differentiated IMR32 cells, which was significantly ameliorated by RUT. Cognitive dysfunction was induced in Wistar rats by administering ten cycles of DOX (2.5 mg/kg, intra-peritoneal, once in 5 days), as we observed significant impairment of episodic memory in ORT. Coadministration with RUT (50 mg/kg, per os) significantly prevented memory deficits in vivo without any confounding influence on locomotor activity. RUT also offered protection against DOX-induced myelosuppression, cardiotoxicity, and nephrotoxicity. In conclusion, RUT may be a possible adjuvant therapeutic intervention to alleviate cognitive and other complications associated with DOX chemotherapy.

Histamine H3 Receptor Antagonist Prevents Memory Deficits and Synaptic Plasticity Disruption Following Isoflurane Exposure.

Exposure to pharmacological concentration of inhaled anesthetics such as isoflurane can cause short- or long-term cognitive impairments in preclinical studies. The selective antagonists of the histamine H3 receptors are considered as a promising group of novel therapeutic agents for the treatment of cognitive disorders. In this study, we investigated whether ciproxifan, a nonimidazole antagonist of H3 histamine receptors, could overcome the functional and electrophysiological sequela associated with isoflurane anesthesia. Adult male Sprague Dawley rats were exposed to 1.4% isoflurane or vehicle gas for 2 h. The memory tests (novel object recognition and passive avoidance) as well as in vivo hippocampal excitatory synaptic potentials were recorded 24 h postanesthesia. Locomotor activity, anxiety, and nociception 24 h after isoflurane were also examined. The drugs (ciproxifan 3 mg/kg or saline) were intraperitoneally injected 30 min prior to the behavioral tests or long-term potentiation induction. Animals that were previously (24 h) exposed to 1.4% isoflurane for 2 h displayed no preference for novel objects and had impaired retention of a passive avoidance response at 1 h after sample phase. Treating isoflurane-exposed rats with ciproxifan significantly improved the memory performance, as evidenced by an increased discrimination ratio in objects recognition and prolonged retention time in passive avoidance test. Accordingly, hippocampus long-term potentiation was reduced in animals that received isoflurane, while administration of ciproxifan completely abolished the effect of isoflurane exposure on synaptic plasticity. Neither isoflurane nor ciproxifan altered motor performance, anxiety, and nociceptive responses. These results suggest that H3R in the CNS, probably in the hippocampus, may serve as therapeutic target for improvement of anesthesia-associated cognitive deficits.

Caspase-2 cleavage of tau reversibly impairs memory.

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Guanosine Prevents Anhedonic-Like Behavior and Impairment in Hippocampal Glutamate Transport Following Amyloid-β1-40 Administration in Mice.

Amyloid-beta (Aβ) peptides are the major neuropathological hallmarks related with Alzheimer's disease (AD). Aβ peptides trigger several biochemical mechanisms of neurotoxicity, including neuroinflammation and glutamatergic neurotransmission impairment. Guanosine is the endogenous guanine-derived nucleoside that modulates the glutamatergic system and the cellular redox status, thus acting as a neuroprotective agent. Here, we investigated the putative neuroprotective effect of guanosine in an AD-like mouse model. Adult mice received a single intracerebroventricular injection of Aβ1-40 (400pmol/site) or vehicle and then were treated immediately, 3h later, and once a day during the subsequent 14days with guanosine (8mg/kg, intraperitoneally). Aβ1-40 or guanosine did not alter mouse locomotor activity and anxiety-related behaviors. Aβ1-40-treated mice displayed short-term memory deficit in the object location task that was prevented by guanosine. Guanosine prevented the Aβ1-40-induced increase in latency to grooming in the splash test, an indicative of anhedonia. Aβ1-40 increased Na+-independent glutamate uptake in ex vivo hippocampal slices, and guanosine reversed it to control levels. The repeated administration of guanosine increased hippocampal GDP levels, which was not observed in the group treated with Aβ plus guanosine. Aβ1-40 induced an increase in hippocampal ADP levels. Aβ1-40 decreased GFAP expression in the hippocampal CA1 region, an effect not modified by guanosine. No differences were observed concerning synaptophysin and NeuN immunolabeling. Together, these results show that guanosine prevents memory deficit and anhedonic-like behavior induced by Aβ1-40 that seem to be linked to glutamate transport unbalance and alterations on purine and metabolite levels in mouse hippocampus.

Resveratrol limits diabetes-associated cognitive decline in rats by preventing oxidative stress and inflammation and modulating hippocampal structural synaptic plasticity

Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Resveratrol, a polyphenol found mainly in grapes and red wine, has antioxidant, anti-inflammatory, and neuroprotective activities. Studies demonstrated that resveratrol could prevent memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. However, whether administration of resveratrol could modulate the structural synaptic plasticity in diabetic rats remains unknown. Therefore, we tested its influence against cognitive dysfunction as well as on hippocampal structural synaptic plasticity in streptozotocin-induced diabetic rats. Our results showed that the cognitive performances in diabetic group were markedly deteriorated, accompanied by noticeable alterations in oxidative as well as inflammation parameters, SYN and GAP-43 expression were reduced in the hippocampus. In contrast, chronic treatment with resveratrol (10, 20mg/kg) improved neuronal injury and cognitive performance by attenuating oxidative stress and inflammation as well as inhibiting synapse loss in diabetic rats. In conclusion, the present study suggested that oral supplementation of resveratrol might be a potential therapeutic strategy for the treatment and/or prevention of diabetic encephalopathy.

An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice.

The pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1-42 peptide. Seven days after Aβ1-42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1-42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1-42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.

Identification of Novel Key Molecules Involved in Spatial Memory Impairment in Triple Transgenic Mice of Alzheimer's Disease.

The molecular mechanisms underlying cognitive impairment in Alzheimer's disease (AD) remain largely unclear. In the present study, we were aimed to identify the potential key molecules involved in spatial memory impairment in a triple transgenic (3xTg-AD) mouse model of AD. By employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 24 differentially expressed proteins in hippocampus of 9-month-old 3xTg-AD mice with significant spatial memory impairment in comparison to the age-matched controls. These differentially expressed proteins can be categorized into several functional classifications that are related to synaptic/memory-, energy metabolism-, intracellular transport-, cell cycle-, cellular defense and structure, and stress response. To further verify the target proteins that may underlie the memory deficits, we pre-treated the 3xTg-AD mice for 3months with coenzyme Q10 (CoQ10) (800mg/kg body weight/day), a powerful endogenous antioxidant that has been shown to be able to prevent memory deficits in several AD mouse models. We found that administration of CoQ10 altered the expression levels of nine proteins in hippocampus of 3xTg-AD mice with simultaneous improvement of spatial memory. Interestingly, complexin-1/2, two molecules which were shown to alter LTP, were modulated (i.e., the levels were reduced in 3xTg-AD mice and CoQ10 restored the levels) in response to CoQ10 treatment among these nine proteins. Furthermore, we found that adeno-associated virus serotype 9 (AAV-9)-mediated overexpression of complexin-1/2 prevented memory impairment in the AD mouse model. Taken together, this study has identified a number of differentially expressed proteins in hippocampus of 3xTg-AD mice and the control in presence or absence of CoQ10. The modulation of complexin-1/2 expression by CoQ10 may contribute to the amelioration of memory impairment in the AD transgenic mice.

The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer’s disease

Increasing evidence suggests that disruptions of synaptic functions correlate with the severity of cognitive deficit in Alzheimer’s disease (AD). Our previous study demonstrated that baicalein enhances long-term potentiation (LTP) in acute rat hippocampal slices and improves hippocampus-dependent contextual fear conditioning in rats. Given that baicalein possess various biological activities, especially its effects on synaptic plasticity and cognitive function, we examined the effect of baicalein on synaptic function both in vitro and in vivo in AD model. The effect of baicalein on Aβ42 oligomer impaired LTP was investigated by electrophysiological methods. Baicalein was administered orally via drinking water to the APP/PS1 mice and sex- and age-matched wild-type mice. Treatment started at 5 months of age and mice were assessed for cognition and AD-like pathology at 7-month-old. Cognition was analyzed by Morris water maze test, fear conditioning test, and novel object recognition test. Changes in hippocampal 12/15 Lipoxygenase (12/15LO) and glycogen synthase kinase 3β (GSK3β) activity, Aβ production, tau phosphorylation, synaptic plasticity, and dendritic spine density were evaluated. Baicalein prevented Aβ-induced impairments in hippocampal LTP through activation of serine threonine Kinase (Akt) phosphorylation. Long-term oral administration of baicalein inhibited 12/15LO and GSK3β activity, reduced β-secretase enzyme (BACE1), decreased the concentration of total Aβ, and prevented phosphorylation of tau in APP/PS1 mice. Meanwhile, baicalein restored spine number, synaptic plasticity, and memory deficits. Our results strengthen the potential of the flavonoid baicalein as a novel and promising oral bioactive therapeutic agent that prevents memory deficits in AD.

Piracetam prevents memory deficit induced by postnatal propofol exposure in mice

Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis.

Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats

AimsThe present study aimed to explore the preventive or therapeutic effect of peri-operative pregabalin treatment on the memory deficits and related hippocampal inflammation following surgery in aged rats. Main methodsAged rats underwent abdominal or sham surgery, and were then divided into 2 groups, either early or late pregabalin treatment. Fourteen days after surgery, the cognitive function was assessed using novel object recognition test, followed by measurement of hippocampal cytokines and voltage-dependent calcium channel α2δ subunit (CACNA2D1). The parabiotic experiments determined whether the humoral or neuronal pathway was involved in the neuroinflammation development following the abdominal surgery. The effects of pregabalin on LPS-induced cytokine release from hippocampal microglia were also evaluated. Key findingsEarly pregabalin treatment, which was administered pre-operatively and continued for 3 or 7days after surgery, prevented memory deficits and decreased hippocampal pro-inflammatory cytokine levels. In contrast, no beneficial effects were observed when pregabalin was administered late in the post-operative period. The hippocampal levels of CACNA2D1 did not change under any experimental condition. The data from the cross-circulation (parabiosis) experiments indicated that abdominal surgery may induce neuroinflammation via a neural transmission pathway from the periphery to the brain. The ex vivo experiments further demonstrated that pregabalin had no effect on LPS-induced cytokines release from hippocampal microglia. SignificanceOur findings highlight reveal that peri-operative pregabalin treatment during the early post-operative period can prevent neuroinflammation and memory deficits after surgery. It is likely this occurs through a peripheral and central neuro-immune interaction rather than through direct anti-inflammatory effects.

Amitriptyline and phenytoin prevents memory deficit in sciatic nerve ligation model of neuropathic pain.

Phenytoin and amitriptyline are often reported to attenuate pain in chronic conditions. Information on their ability to ameliorate cognitive impairment associated with neuropathic pain remains unclear due to mixed results from studies. This study investigated the effects of phenytoin and amitriptyline on memory deficit associated with neuropathic pain. Twenty-eight adult male Wistar rats were randomly divided into four groups: A, B, C, and D (n=7). Groups A, B, C, and D served as sham control, sciatic nerve ligated untreated, sciatic nerve ligated receiving amitriptyline (5 mg/kg), and sciatic nerve ligated receiving phenytoin (10 mg/kg) respectively. Treatments lasted for 14 days, after which both 'Y' maze and novel object recognition test (NOR) were performed. On the last day of treatment, the animals were anesthetized and their brain excised, and the prefrontal cortices and sciatic nerve were processed histologically using hematoxylin and eosin. There was memory impairment in the sciatic nerve ligated untreated group which was statistically significant (p<0.05) when compared to the phenytoin-treated, amitriptyline-treated, and sham control groups using the 'Y' maze and NOR tests. Histological quantification showed that the prefrontal cortices of the ligated animals showed increased neural population in comparison to normal control. These increases were significantly marked in the untreated ligated group. Sciatic nerve of untreated ligated group showed high demyelination and axonal degeneration which was ameliorated in the treated animals. The administration of amitriptyline and phenytoin can ameliorate neuronal injury, demyelination, and memory impairment associated with neuropathic pain in Wistar rats.

Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus.

Asiatic acid is a pentacyclic triterpene from Centella asiatica. Previous studies have reported that asiatic acid exhibits antioxidant and neuroprotective activities in cell culture. It also prevents memory deficits in animal models. The objective of this study was to investigate the relationship between spatial working memory and changes in cell proliferation within the hippocampus after administration of asiatic acid to male Spraque-Dawley rats. Control rats received vehicle (propylene glycol) while treated rats received asiatic acid (30 mg/kg) orally for 14 or 28 days. Spatial memory was determined using the novel object location (NOL) test. In animals administered asiatic acid for both 14 and 28 days, the number of Ki-67 positive cells in the subgranular zone of the dentate gyrus was significantly higher than in control animals. This was associated with a significant increase in their ability to discriminate between novel and familiar object locations in a novel object discrimination task, a hippocampus-dependent spatial memory test. Administration of asiatic acid also significantly increased doublecortin (DCX) and Notch1 protein levels in the hippocampus. These findings demonstrate that asiatic acid treatment may be a potent cognitive enhancer which improves hippocampal-dependent spatial memory, likely by increasing hippocampal neurogenesis.