Reversed Memory Impairment Research Articles

Astragaloside IV as a Memory-Enhancing Agent: In Silico Studies with In Vivo Analysis and Post Mortem ADME-Tox Profiling in Mice.

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus, to attenuate memory impairment. Scopolamine (SCOP), an antagonist of muscarinic cholinergic receptors, and lipopolysaccharide (LPS), a trigger of neuroinflammation, were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in SCOP-treated mice was attenuated by prior intraperitoneal (ip) administration of AIV at a dose of 25 mg/kg. The attenuation of memory impairment by LPS was not observed. It can therefore be assumed that AIV does not reverse memory impairment by anti-inflammatory mechanisms, although this needs to be further verified. All doses of AIV tested did not affect baseline locomotor activity in mice. In the post mortem analysis by mass spectrometry of the body tissue of the mice, the highest content of AIV was found in the kidneys, then in the spleen and liver, and the lowest in the brain.

Interaction effect of crocin and citalopram on memory and locomotor activity in rats: an insight into BDNF and synaptophysin levels in the hippocampus.

Selective serotonin reuptake inhibitors (SSRIs) are widely used drugs for the treatment of depression. Citalopram is one of the most prescribed SSRIs that is useful for the treatment of depression, obsessive-compulsive disorder, and anxiety disorders. On the other hand, crocin (active constitute of saffron) has pro-cognitive and mood enhancer effects. Also, both citalopram and crocin affect the function and expression of brain-derived neurotrophic factor (BDNF) and synaptophysin, two molecular factors that are involved in cognitive functions and mood. In the present study, we aim to investigate the interaction effect of citalopram and crocin on rats' performance in the open field test (locomotor activity and anxiety-like behavior) and the shuttle box (passive avoidance memory). Citalopram was injected at the doses of 10, 30, and 50mg/kg, and crocin was injected at the dose of 50mg/kg; all administrations were intraperitoneal. Real-time PCR was used to assess the expression level of BDNF and synaptophysin in the hippocampus. The results showed that citalopram (30 and 50mg/kg) impaired passive avoidance memory and decreased BDNF and synaptophysin expression in the hippocampus, while crocin reversed memory impairment, and BDNF and synaptophysin expression in the hippocampus of rats received citalopram 30mg/kg. Also, crocin partially showed these effects in rats that received citalopram 50mg/kg. The results of the open field test were unchanged. In conclusion, we suggested that BDNF and synaptophysin may be involved in the effects of both citalopram and crocin.

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aβ1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.

Class I histone deacetylases inhibition reverses memory impairment induced by acute stress in mice.

While chronic stress induces learning and memory impairments, acute stress may facilitate or prevent memory consolidation depending on whether it occurs during the learning event or before it, respectively. On the other hand, it has been shown that histone acetylation regulates long-term memory formation. This study aimed to evaluate the effect of two inhibitors of class I histone deacetylases (HDACs), 4-phenylbutyrate (PB) and IN14 (100 mg/kg/day, ip for 2 days), on memory performance in mice exposed to a single 15-min forced swimming stress session. Plasma corticosterone levels were determined 30 minutes after acute swim stress in one group of mice. In another experimental series, independent groups of mice were trained in one of three different memory tasks: Object recognition test, Elevated T maze, and Buried food location test. Subsequently, the hippocampi were removed to perform ELISA assays for histone deacetylase 2 (HDAC2) expression. Acute stress induced an increase in plasma corticosterone levels, as well as hippocampal HDAC2 content, along with an impaired performance in memory tests. Moreover, PB and IN14 treatment prevented memory loss in stressed mice. These findings suggest that HDAC2 is involved in acute stress-induced cognitive impairment. None of the drugs improved memory in non-stressed animals, indicating that HDACs inhibitors are not cognitive boosters, but rather potentially useful drugs for mitigating memory deficits.

Melanotan-II reverses memory impairment induced by a short-term HF diet

A high-fat (HF) diet has been shown to increase the risk of neurological impairments and neurodegenerative disorders. The melanotropins used in this study have been associated with diet-related disorders; however, there is an absence of studies on their effect on diet-induced neurobehavioral conditions. Here, we investigated the possible relationship among diet, Melanotan-II (MT-II) targeting melanotropin receptors, and the behavior of zebrafish (Danio rerio). Surprisingly, even a short-term HF diet lasting for ∼ 1 % of the zebrafish's life had a strong developmental effect. Zebrafish fed the HF diet showed an impairment in recognition memory, elevated anxiety levels, and reduced exploratory propensity after just three weeks compared to zebrafish fed the control diet. These HF diet-induced abnormalities were reversed by MT-II. Animals fed a HF diet and treated with MT-II demonstrated recognition memory, anxiety, and exploratory behavior similar to the control group. This study provides evidence that even a short-term HF diet has an impact on memory and emotions and is the first study to show that MT-II reverses these changes.

Multisensory Stimulation Reverses Memory Impairment in Adrβ3KO Male Mice.

Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrβ: β1, β2 and β3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrβ3 (Adrβ3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrβ3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrβ3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrβ3KO mice. In the AMY of Adrβ3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrβ3KO animals and indicates that the control of neuroinflammation mediates this response.

A high-salt diet induces synaptic loss and memory impairment via gut microbiota and butyrate in mice.

High-salt diet (HSD)-fed mice display cognitive impairment and lower synaptic proteins via changed gut microbiota composition and short-chain fatty acids production. Gut microbiota from HSD-fed mice impairs memory and synapse in normal salt diet-fed mice. Butyrate treatment partially reverses memory impairment in HSD-fed mice. Above all, this study indicates the important role of the gut microbiome and butyrate production in synaptic loss and memory impairment.

Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-β (Aβ) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aβ toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aβ followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4months. We observed that HH treatment ameliorated memory impairment and reduced Aβ deposits in the brains of the mice. HH directly inhibited Aβ aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement.

Aniba canelilla (Kunth) Mez essential oil and its primary constituent, 1-nitro-2-phenylethane, inhibits acetylcholinesterase and reverse memory impairment in rodents

Ethnopharmacological relevanceAniba canelilla, distributed in the Amazon region, stands out for its diverse economic and medicinal applications. Studies of the A. canelilla essential oil and its primary constituent, 1-nitro-2-phenylethane, have confirmed its anti-inflammatory, antinociceptive, anti-hypertensive potential, and anticholinesterase, among other therapeutic activities.Aim of the study: In addition, the present work aims to evaluate the potential of oil and NPE in the learning and memory of rodents. Material and methodsThe oil was hydrodistilled and analyzed by GC and GC-MS. The learning and memory action in mice was evaluated through the scopolamine-induced cognitive deficit model, followed by behavioral analysis using Morris's water maze paradigm. ResultsOil provided a yield of 0.5%, and in its chemical composition, 1-nitro-2-phenylethane (NPE) (76.2%) and methyleugenol (19.6%) were identified as primary constituents. Oil fractionation furnished NPE with 99.4%, which was used to evaluate its effects in animal models. Wistar rats were submitted to the mnemonic impairment-scopolamine-induced protocol for 7 days. The oil, NPE, and the positive control donepezil were administered from the 8th to 12th days. Morris water maze results demonstrated that oil and NPE reversed spatial learning and long-term memory similarly induced by muscarinic antagonist scopolamine to donepezil, the positive control. ConclusionThese beneficial effects have led the work to further investigations of the oil and NPE to elucidate their pharmacological mechanism, focusing on the cholinergic pathway of the central nervous system and opening up to the knowledge of other adjacent mechanisms, whose results are still under analysis.

Callus Culture of Scorzonera radiata as a New, Highly Productive and Stable Source of Caffeoylquinic Acids.

During our ongoing efforts to investigate biotechnological sources of caffeoylquinic acid (CQA) metabolites, we discovered the plant Scorzonera radiata Fisch. (Asteraceae), which is able to produce callus cultures with high yield and extremely high stability. An actively growing callus line, designated as Sr-L1, retained the ability to produce 11 CQAs during long-term cultivation (more than 20 years). A total of 29 polyphenolic compounds were identified in the leaves and Sr-L1 callus culture of S. radiata, including CQAs, lignol derivatives, flavonoids, and dihydrostilbenes. The composition of CQAs in the Sr-L1 culture was identical to that in the S. radiata leaves. Sr-L1 calli did not produce flavonoids and dihydrostilbenes, but produced lignol derivatives, which were absent in leaves. The HPLC-UV-HRMS determination showed the presence of monoacyl derivatives of CQAs such as 5-CQA, 4-CQA, cis-5-CQA, and 5-O-p-coumaroylquinic acid in the Sr-L1 culture. Among diacyl derivatives, 3,4-diCQA, 3,5-diCQA, cis-3,5-diCQA, 4,5-diCQA, 3-O-p-coumaroyl-5-O-CQA, and 3-O-caffeoyl-5-O-p-coumaroylquinic acid were found. The content of 5-CQA reached 7.54 mg/g dry weight and the content of 3,5-diCQA was as high as 18.52 mg/g dry weight. 3,5-diCQA has been reported to be of high nutritional and pharmacological value, as it alleviates inflammatory pain, reverses memory impairment by preventing neuronal apoptosis, and counteracts excessive adipose tissue expansion, serving as an attractive treatment option for obesity. The high content of 3,5-diCQA and the exceptional stability of biosynthesis make callus cultures of S. radiata a promising source for the development of drugs and nutraceuticals.

Effect of cx-DHED on Abnormal Glucose Transporter Expression Induced by AD Pathologies in the 5xFAD Mouse Model.

Alzheimer’s disease (AD) is a form of dementia associated with abnormal glucose metabolism resulting from amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau protein tangles. In a previous study, we confirmed that carboxy-dehydroevodiamine∙HCl (cx-DHED), a derivative of DHED, was effective at improving cognitive impairment and reducing phosphorylated tau levels and synaptic loss in an AD mouse model. However, the specific mechanism of action of cx-DHED is unclear. In this study, we investigated how the cx-DHED attenuates AD pathologies in the 5xFAD mouse model, focusing particularly on abnormal glucose metabolism. We analyzed behavioral changes and AD pathologies in mice after intraperitoneal injection of cx-DHED for 2 months. As expected, cx-DHED reversed memory impairment and reduced Aβ plaques and astrocyte overexpression in the brains of 5xFAD mice. Interestingly, cx-DHED reversed the abnormal expression of glucose transporters in the brains of 5xFAD mice. In addition, otherwise low O-GlcNac levels increased, and the overactivity of phosphorylated GSK-3β decreased in the brains of cx-DHED-treated 5xFAD mice. Finally, the reduction in synaptic proteins was found to also improve by treatment with cx-DHED. Therefore, we specifically demonstrated the protective effects of cx-DHED against AD pathologies and suggest that cx-DHED may be a potential therapeutic drug for AD.

D-ribose-L-cysteine reduces oxidative stress and inflammatory cytokines to mitigate liver damage, and memory decline induced by copper sulfate in mice

BackgroundCurrent evidences have implicated copper in amyloid aggregation that trigger the downstream oxidative stress-mediated neuroinflammation that characterized memory deterioration in patients with Alzheimer’s disease (AD). Thus, this study was designed to evaluate the effect of D-Ribose-L-Cysteine (DRLC), a potent antioxidant agent, on copper sulfate (CuSO4)-induced memory deterioration and the biochemical mechanisms underpinning its action in mice. MethodsMale Swiss mice were randomly distributed into 5 groups (n = 10/group). Mice in group 1 were given distilled water (control), group 2 CuSO4 (100 mg/kg) while groups 3–5 were pretreated with CuSO4 (100 mg/kg) 30 min before administration of DRLC (10, 25 and 50 mg/kg). Treatments were given through oral gavage, daily for 28 days. Memory function was evaluated on day 28 using Y-maze test. The isolated liver and brain tissues were then processed for oxidative stress biomarkers, and proinflammatory cytokines [tumor necrosis factor- α (TNF-α) and interleukin-6)] assays. Brian acetylcholinesterase (AChE) and liver enzymes [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. ResultsDRLC reversed memory impairment and dysregulated levels of malondialdehyde, glutathione, nitrite and glutathione S-transferase in the liver and brain tissues of mice pretreated with CuSO4. The increased proinflammatory cytokines concentrations in the liver and brain tissues of mice pretreated with CuSO4 were reduced by DRLC. The elevated brain AChE and liver enzymes activities induced by CuSO4 were also reduced by DRLC. ConclusionTaken together, these findings suggest that DRLC attenuates CuSO4-induced memory dysfunctions in mice through enhancement of antioxidative pathway, inhibition of pro-inflammatory cytokines and augmentation of liver function.

Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex.

The encephalitis associated with antibodies against contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but the antibody effects and whether they cause behavioral alterations are not well known. Here, we used a mouse model of patients' immunoglobulin G (IgG) transfer and super-resolution microscopy to demonstrate the antibody pathogenicity. IgG from patients with anti-CASPR2 encephalitis or healthy controls was infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with stimulated emission depletion microscopy (40-70μm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients' IgG. Infusion of patients' IgG, but not controls' IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients' IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients' IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients' IgG. IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches. ANN NEUROL 2022;91:801-813.

Octovespin, a peptide bioinspired by wasp venom, prevents cognitive deficits induced by amyloid-β in Alzheimer's disease mouse model

Approximately 46.8 million people have been diagnosed worldwide with dementia, of which the most common type is Alzheimer's disease (AD). Since the current AD treatment is incipient and limited, it is essential to develop new drugs to prevent AD. Considering that evolutionary pressure selected animal venom compounds that are very specific for a unique target, those can be a potential drug against AD. Octovespin was modified from occidentalin-1202, which is a peptide isolated from Polybia occidentalis wasp venom. In this context, this study evaluated the effect of treatment with octovespin against Amyloid-β (Aβ)-induced toxicity, which is postulated to be one of the main causes of AD, in both in vitro and in vivo tests. In vitro, octovespin was able to prevent Aβ aggregation in a ThT assay. In vivo, octovespin (0.15 nmol/animal) reverses memory impairment that is due to Aβ toxicity, in the Morris Water Maze and Novel Object Recognition Test. Our results suggested that octovespin is a potential drug for the treatment of AD, due to its ability to avoid Aβ aggregation in vitro and to prevent Aβ -induced memory deficit in mice.

Quercetin mitigates memory deficits in scopolamine mice model via protection against neuroinflammation and neurodegeneration

AimsNeurodegenerative disorders like Alzheimer's disease (AD) are outcomes of neuroinflammatory processes that result in memory impairment. Quercetin (QT), a plant based flavonoid, has demonstrated notable effects against neurodegeneration and inflammation in models of dementia. However, the underlying mechanisms have not been well elucidated. This study evaluated the possible effects of QT against neuroinflammation and neurodegeneration in scopolamine (SC) induced memory impairment. Main methodsSC was used to induce memory loss in mice after which novel object recognition test (NORT) was used to assess memory function. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the brain tissues of the animals. Brain histology was carried out on the hippocampus (cornus ammonis 1, cornus ammonis 3 and dentate gyrus), and the prefrontal cortex. The population of healthy neuronal cells was counted, using ImageJ software. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was employed for the identification of cells undergoing apoptosis. Key findingsQT reversed memory impairment in the NORT. Increases in TNF-α and IL-6 were attenuated by QT, and histology revealed that QT attenuated SC-induced cell degeneration and death in the hippocampal sub-regions and prefrontal cortex. QT diminished the population of dead cells in SC-treated mice, and also reversed the process of apoptosis induced by SC. SignificanceFindings from the study suggest that QT mitigates pro-inflammatory mediators and reverses neurodegeneration to restore memory function.

Edaravone prevents memory impairment in diabetic rats: Role of oxidative stress

BackgroundUncontrolled diabetes mellitus (DM) is accompanied by progressive cognitive deterioration mediated by neurodegeneration due to chronic hyperglycemia and subsequent oxidative damage. Oxidative stress damage due to high blood glucose is associated with functional and structural changes in the hippocampus, responsible for cognitive properties, leading to cognitive impairment. Edaravone is a potent antioxidant with neuroprotective properties that has mainly been used to treat amyotrophic lateral sclerosis and has been tested in many models associated with cognition deficits. Our study aimed to assess edaravone's potential neuroprotective activity to reverse memory impairment in a streptozotocin (STZ)-induced diabetic rat model. MethodsDM was induced by a single 50 mg/kg STZ intraperitoneal injection. Rats received edaravone intraperitoneally at 6 mg/kg/day, six days/week, for four weeks. The radial arm water maze behavioral test evaluated both learning and memory. Oxidative stress was evaluated by molecularly measuring hippocampus enzyme activities and biomarker levels. ResultsImpairment of short- and long-term memory was observed in rats with STZ-induced diabetes, accompanied by decreased hippocampal superoxide dismutase and glutathione peroxidase activities and reduced/oxidized glutathione ratio. Edaravone significantly attenuated memory impairment (p < 0.05) and normalized oxidative stress biomarker levels (p < 0.05). Furthermore, STZ significantly increased hippocampal thiobarbituric acid reactive substance activity, which was also normalized by edaravone treatment (p < 0.05). However, STZ and edaravone did not affect catalase and brain-derived neurotrophic factor levels (p > 0.05). ConclusionEdaravone prevented STZ-induced memory impairment and attenuated oxidative stress likely by restoring hippocampus antioxidant mechanisms.

Cannabidiol reverses memory impairments and activates components of the Akt/GSK3β pathway in an experimental model of estrogen depletion

Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3β survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3β pathway’s activation by decreasing the phosphorylation levels of Akt and GSK3β and Bcl2 levels, which were ameliorated by CBD.The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3β survival pathway’s activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.

The piperine derivative HJ105 inhibits Aβ1–42-induced neuroinflammation and oxidative damage via the Keap1-Nrf2-TXNIP axis

BackgroundPiperine is a great lead compound, as a phytopharmaceutical with reported neuroprotective effects in neurodegenerative diseases. HJ105, a piperine derivative with high affinity to Keap1 receptor, attracts increasing attention in Alzheimer's disease (AD) treatment. PurposeThis work mainly aimed to study HJ105’s therapeutic effects on Aβ1–42-associated AD and the underpinning mechanisms. MethodsIn the in vivo part, a rat model of AD was established by bilateral intra-hippocampal administration of aggregated Aβ1–42, followed by a month of intragastric HJ105 or donepezil administration. Spatial and learning memories were detected by the Morris water maze assay, passive avoidance learning as well as Y-maze test. The morphology of hippocampal neurons was assessed by hematoxylin-eosin (H&E) staining. In addition, the amounts of the IL-1β and TNF-α were obtained with specific ELISA kits. More importantly, apoptosis-related proteins and factors involved in Nrf2/TXNIP/NLPR3 pathways were detected by Western blot, while the interaction between Keap1 and Nrf2 was assessed by co-immunoprecipitation. In the in vitro part, human neuroblastoma (SH-SY5Y) cells were applied to evaluate the role of HJ105 on Aβ1–42-induced neuronal damage. ResultsTreatment of HJ105 not only reversed memory impairment, but also protected neurons in the hippocampus by inhibiting Bax/Bcl2 ratio increase. HJ105 decreased TXNIP expression, suppressing NLRP3 inflammasome activation in the hippocampus, which in turn counteracted the upregulation of IL-1β and TNF-α. Notably, HJ105 exerted an inhibitory effect on Keap1-Nrf2 interaction and upregulated nuclear Nrf2, which conversely increased the expression levels of superoxide dismutase, catalase and glutathione peroxidase and downregulated malondialdehyde. Additionally, neurotoxicity induced by Aβ1–42 in SH-SY5Y cells was alleviated by HJ105. ConclusionOverall, HJ105 exerts neuroprotective effects in SH-SY5Y cells induced by Aβ1–42 as well as in experimental rats with AD by decreasing apoptosis, oxidative stress and neuroinflammation, partly via suppression of Keap1-Nrf2 complex generation. HJ105 might represent a promising compound for AD treatment.

Memory impairment in chronic experimental Chagas disease: Benznidazole therapy reversed cognitive deficit in association with reduction of parasite load and oxidative stress in the nervous tissue.

Memory impairment has been associated with chronic Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. In degenerative diseases, memory loss has been associated with increased oxidative stress, revealed as enhanced lipid peroxidation, in the cerebral cortex. Benznidazole (Bz), a trypanocidal drug efficient to reduce blood parasite load in the acute and chronic phases of infection, showed controversial effects on heart disease progression, the main clinical manifestation of CD. Here, we evaluated whether C57BL/6 mice infected with the Colombian type I T. cruzi strain present memory deficit assessed by (i) the novel object recognition task, (ii) the open field test and (iii) the aversive shock evoked test, at 120 days post infection (dpi). Next, we tested the effects of Bz therapy (25mg/Kg/day, for 30 consecutive days) on memory evocation, and tried to establish a relation between memory loss, parasite load and oxidative stress in the central nervous system (CNS). At 120 dpi, T. cruzi-infected mice showed memory impairment, compared with age-matched non-infected controls. Bz therapy (from 120 to 150 dpi) hampered the progression of habituation and aversive memory loss and, moreover, reversed memory impairment in object recognition. In vehicle-administered infected mice, neuroinflammation was absent albeit rare perivascular mononuclear cells were found in meninges and choroid plexus. Bz therapy abrogated the infiltration of the CNS by inflammatory cells, and reduced parasite load in hippocampus and cerebral cortex. At 120 and 150 dpi, lipid peroxidation was increased in the hippocampus and cortex tissue extracts. Notably, Bz therapy reduced levels of lipid peroxidation in the cerebral cortex. Therefore, in experimental chronic T. cruzi infection Bz therapy improved memory loss, in association with reduction of parasite load and oxidative stress in the CNS, providing a new perspective to improve the quality of life of Chagas disease patients.

The role of cyclooxygenase 2 in the cognitive impairment induced by alcohol or stress in rats

Background:Cognitive impairment is an unpleasant and progressive mental disorder characterized by learning and memory disabilities. Stress and alcohol are two known environmental factors that increase cognitive impairment. This study was designed to evaluate the relative role of cyclooxygenase 2 in alcohol or stress-induced cognitive impairment.Materials and Methods:Male Wistar rats were randomly divided into groups with six rats in each. The groups included sham, control, alcohol (15% ethanol in drinking water), and restraint stress (restraint 6 h per day). Three separated groups received celecoxib at a dose of 20 mg/kg in addition to those listed above. The treatments continued daily for 28 days. The object recognition task (ORT) and Morris water maze (MWM) are used to evaluate the learning and memory.Results:Alcohol or restrain stress significantly increased the time and distance needed to find the hidden platform in MWM. Furthermore, they decreased the recognition index in ORT compared to the control group. Administration of celecoxib significantly decreased the required time and traveled distance to reach the platform in alcohol-treated animals but not in the stress-exposed rats. Celecoxib also significantly increased the recognition index both in alcohol- or restraint stress-exposed animals.Conclusion:We found that either alcohol or restraint stress impairs memory in rats. In MWM, celecoxib improved the alcohol-induced memory impairment but could not show a reduction in memory deterioration due to restraint stress. In ORT, celecoxib reversed memory impairment due to both alcohol and restraint stress.