Novel Object Recognition Research Articles

Low-dose lithium adjunct to quetiapine improves cognitive task performance in mice with MK801-induced long-term cognitive impairment: Evidence from a pilot study

BackgroundLow-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment. MethodsThe present study used in vivo Ca2+ imaging and a battery of cognitive function assessments to investigate the long-term effects of LD-Li on cognition in mice exposed to repeated injections of MK801. Prefrontal Ca2+ activity was visualized to estimate alterations in neural activity in the model mice. Pre-pulse inhibition (PPI), novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FC) tasks were used to characterize cognitive performance; open field activity (OFA) testing was used to observe psychotic symptoms. Two treatment strategies were tested: LD-Li [250 mg/d human equivalent dose (HED)] adjunct to quetiapine (QTP; 600 mg/d HED); and QTP-monotherapy (mt; 600 mg/d HED). ResultsCompared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model. LimitationsThere is no medical consensus regarding lithium use in patients with schizophrenia. ConclusionMore pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.

Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model.

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

The memory impairment by hypothyroidism in mice is dependent on time-of-day and sex

Hypothyroidism is an endocrine-metabolic disorder, and as such it compromises a wide range of physiological functions. Memory deficits and, the most recently described, circadian rhythm disruption are among the impairments caused by thyroid dysfunctions. However, although highly likely, there is no evidence connecting these two effects of hypothyroidism. Here, we hypothesized the time-of-day interferes with the memory deficit caused by hypothyroidism. C57BL/6 J mice from both sexes were subjected to novel object recognition (NOR) task during the rest and active phases, corresponding to ZT 2–4 and 14–16, respectively (ZT: Zeitgeber time; ZT 0: lights on at 07:00 am). First, we showed that neither sex nor ZT altered object recognition memory (ORM) in euthyroid mice. Next, animals were divided into control (euthyroid) and hypothyroid [induced with methimazole (0.01%) and perchlorate (0.1%) treatment in the drinking water for 21 days] groups. Under euthyroid conditions, male and female mice recognized the novel object regardless of the time-of-day. However, hypothyroidism impaired ORM at rest phase (ZT 2–4) in both sexes. Surprisingly, in the active phase (ZT 14–16), the hypothyroid males performed the NOR, though a longer time to execute the task was required. In contrast, female hypothyroid mice showed a greater impairment in ORM. Our results suggest that hypothyroidism may disrupt the circadian rhythm in brain areas related to mnemonic processes since in euthyroid condition ORM is not affected by the time-of-day. Furthermore, our findings in an animal model indicate a pronounced deleterious effect of hypothyroidism in women.

A Mild Dose of Aspirin Promotes Hippocampal Neurogenesis and Working Memory in Experimental Ageing Mice.

Aspirin has been reported to prevent memory decline in the elderly population. Adult neurogenesis in the hippocampus has been recognized as an underlying basis of learning and memory. This study investigated the effect of aspirin on spatial memory in correlation with the regulation of hippocampal neurogenesis and microglia in the brains of ageing experimental mice. Results from the novel object recognition (NOR) test, Morris water maze (MWM), and cued radial arm maze (cued RAM) revealed that aspirin treatment enhances working memory in experimental mice. Further, the co-immunohistochemical assessments on the brain sections indicated an increased number of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive newly generated neurons in the hippocampi of mice in the aspirin-treated group compared to the control group. Moreover, a reduced number of ionized calcium-binding adaptor molecule (Iba)-1-positive microglial cells was evident in the hippocampus of aspirin-treated animals. Recently, enhanced activity of acetylcholinesterase (AChE) in circulation has been identified as an indicative biomarker of dementia. The biochemical assessment in the blood of aspirin-treated mice showed decreased activity of AChE in comparison with that of the control group. Results from this study revealed that aspirin facilitates hippocampal neurogenesis which might be linked to enhanced working memory.

Ameliorative effects of probiotics in AlCl3-induced mouse model of Alzheimer's disease.

In recent years, gut microbiome alterations have been linked with complex underlying mechanisms of neurodegenerative disorders including Alzheimer's disease (AD). The gut microbiota modulates gut brain axis by facilitating development of hypothalamic-pituitary-adrenal axis and synthesis of neuromodulators. The study was designed to unravel the effect of combined consumption of probiotics; Lactobacillus rhamnosus GG (LGG®) and Bifidobacterium BB-12 (BB-12®) (1 × 109CFU) on AlCl3-induced AD mouse model in comparison with potent acetylcholine esterase inhibitor drug for AD, donepezil. Mice were randomly allocated to six different study groups (n = 8). Behavioral tests were conducted to assess effect of AlCl3 (300mg/kg) and probiotics treatment on cognition and anxiety through Morris Water Maze (MWM), Novel Object Recognition (NOR), Elevated Plus Maze (EPM), and Y-maze. The results indicated that the combined probiotic treatment significantly (p < 0.0001) reduced anxiety-like behavior post AlCl3 exposure. The AlCl3 + LGG® and BB-12®-treated group showed significantly improved spatial (p < 0.0001) and recognition memory (p < 0.0001) in comparison to AlCl3-treated group. The expression status of inflammatory cytokines (TNF-α and IL-1β) was also normalized upon treatment with LGG® and BB-12® post AlCl3 exposure. Our findings indicated that the probiotics LGG® and BB-12® have strong potential to overcome neuroinflammatory imbalance, cognitive deficits and anxiety-like behavior, therefore can be considered as a combination therapy for AD through modulation of gut brain axis. KEY POINTS: • Bifidobacterium BB-12 and Lactobacillus rhamnosus GG were fed to AlCl3-induced Alzheimer's disease mice. • This combination of probiotics had remarkable ameliorating effects on anxiety, neuroinflammation and cognitive deficits. • These effects may suggest that combined consumption of these probiotics instigate potential mitigation of AD associated consequences through gut brain axis modulation.

Neuroprotective effects of Petiveria alliacea on scopolamine-induced learning and memory impairment mouse model

Ethnopharmacology relevancePetiveria alliacea L., commonly known as macura and gully root, is an important medicinal plant used in the Caribbean and Central America to treat ailments associated to the central nervous system, including poor memory. Aim of the studyTo assess the effects of the P. alliacea leaves methanol fraction (PMF) on a scopolamine-induced learning and memory impairment mouse model related to acetylcholinesterase activity and oxidative stress. Material and methodsAfter PMF administration at doses of 500 or 900 mg/kg, cognitive ability was evaluated using the Morris water maze (MWM), Y-maze (YM) and novel object recognition (NOR) tests. The mouse brain tissue was further assessed for acetylcholinesterase activity and antioxidant activity. Levels of oxidative stress were also evaluated by measuring malondialdehyde (MDA) and glutathione activity. Acute toxicity was also evaluated. ResultsPMF led to memory improvement in the behavioral tests in mice with scopolamine-induced cognitive impairment. Moreover, PMF inhibited acetylcholinesterase activity and showed antioxidant potential that in turn attenuated cholinergic degradation. Additionally, PMF increased glutathione levels and glutathione reductase activity and reduced MDA levels in the brain. Moreover, no acute toxicity was detected with the use of PMF. ConclusionIn a mouse model of scopolamine-induced cognitive deficit, PMF exhibited protective effects, decreasing oxidative damage and regulating cholinergic function in the brain bearing significant memory enhancing potency. These data suggest that PMF is a promising candidate for developing therapies for neurodegenerative disorders.

Quetiapine Moderates Doxorubicin-Induced Cognitive Deficits: Influence of Oxidative Stress, Neuroinflammation, and Cellular Apoptosis.

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress.

Sepsis exacerbates Alzheimer's disease pathophysiology, modulates the gut microbiome, increases neuroinflammation and amyloid burden.

While our understanding of the molecular biology of Alzheimer's disease (AD) has grown, the etiology of the disease, especially the involvement of peripheral infection, remains a challenge. In this study, we hypothesize that peripheral infection represents a risk factor for AD pathology. To test our hypothesis, APP/PS1 mice underwent cecal ligation and puncture (CLP) surgery to develop a polymicrobial infection or non-CLP surgery. Mice were euthanized at 3, 30, and 120 days after surgery to evaluate the inflammatory mediators, glial cell markers, amyloid burden, gut microbiome, gut morphology, and short-chain fatty acids (SCFAs) levels. The novel object recognition (NOR) task was performed 30 and 120 days after the surgery, and sepsis accelerated the cognitive decline in APP/PS1 mice at both time points. At 120 days, the insoluble Aβ increased in the sepsis group, and sepsis modulated the cytokines/chemokines, decreasing the cytokines associated with brain homeostasis IL-10 and IL-13 and increasing the eotaxin known to influence cognitive function. At 120 days, we found an increased density of IBA-1-positive microglia in the vicinity of Aβ dense-core plaques, compared with the control group confirming the predictable clustering of reactive glia around dense-core plaques within 15 μm near Aβ deposits in the brain. In the gut, sepsis negatively modulated the α- and β-diversity indices evaluated by 16S rRNA sequencing, decreased the levels of SCFAs, and significantly affected ileum and colon morphology in CLP mice. Our data suggest that sepsis-induced peripheral infection accelerates cognitive decline and AD pathology in the AD mouse model.

Neuroprotective potency of mangiferin against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats: possible antioxidant and anti-inflammatory mechanisms.

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of psychiatric disturbances, cognitive and motor dysfunction. The daily performances and life quality of HD patients have been severely interfered by these clinical signs and symptoms until the last stage of neuronal cell death. To the best of our knowledge, no treatment is available to completely mitigate the progression of HD. Mangiferin, a naturally occurring potent glucoxilxanthone, is mainly isolated from the Mangifera indica plant. Considerable studies have confirmed the medicinal benefits of mangiferin against memory and cognitive impairment in neurodegenerative experimental models such as Alzheimer's and Parkinson's diseases. Therefore, this study aims to evaluate the neuroprotective effect of mangiferin against 3-nitropropionic acid (3-NP) induced HD in rat models. Adult Wistar rats (n = 32) were randomly allocated equally into four groups of eight rats each: normal control (Group I), disease control (Group II) and two treatment groups (Group III and Group IV). Treatment with mangiferin (10 and 20mg/kg, p. o.) was given for 14days, whereas 3-NP (15mg/kg, i. p.) was given for 7days to induce HD-like symptoms in rats. Rats were assessed for cognitive functions and motor coordination using open field test (OFT), novel object recognition (NOR) test, neurological assessment, rotarod and grip strength tests. Biochemical parameters such as oxidative stress markers and pro-inflammatory markers in brain hippocampus, striatum and cortex regions were evaluated. Histopathological study on brain tissue was also conducted using hematoxylin and eosin (H&E) staining. 3-NP triggered anxiety, decreased recognition memory, reduced locomotor activity, lower neurological scoring, declined rotarod performance and grip strength were alleviated by mangiferin treatment. Further, a significant depletion in brain malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) level, succinate dehydrogenase (SDH), superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels were observed in mangiferin treated groups. Mangiferin also mitigated 3-NP induced histopathological alteration in the brain hippocampus, striatum and cortex sections. It could be inferred that mangiferin protects the brain against oxidative damage and neuroinflammation, notably via antioxidant and anti-inflammatory activities. Mangiferin, which has a good safety profile, may be an alternate treatment option for treating HD and other neurodegenerative disorders. The results of the current research of mangiferin will open up new avenues for the development of safe and effective therapeutic agents in diminishing HD.

Edaravone Improves Streptozotocin-Induced Memory Impairment via Alleviation of Behavioral Dysfunction, Oxidative Stress, Inflammation, and Histopathological Parameters.

Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990–1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or lipopolysaccharide (LPS, 30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

Activation of Metabotropic Glutamate Receptor (mGlu2) and Muscarinic Receptors (M1, M4, and M5), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression and cGMP Synthesis.

The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M1, M4, and M5 receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu2 receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression.

Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems

Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1β, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80–160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model

RationaleMaternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. ObjectivesThe aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. MethodsFemale Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. ResultsPoly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. ConclusionsThese results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.

Agmatine prevents the memory impairment and the dysfunction of hippocampal GSK-3β and ERK signaling induced by aluminum nanoparticle in mice.

The growing usage of aluminum nanoparticles (Al-NP) and their exposure may influence body function. Considering the proposed relationship between Al and the pathogenesis of Alzheimer's disease and the concern about the effect of this nanoparticle on brain health and cognitive function, the use of neuroprotective agents might be helpful. According to the reported neuroprotective effects of agmatine, in the present study, the possible protective effect of agmatine was assessed in mice model of Al-NP-induced memory impairment. In addition, due to the roles of hippocampal Glycogen synthase kinase-3 beta (GSK-3β) and ERK signaling in memory and its disorders, these pathways were also investigated. Al-NP (10 mg/kg/p.o.) with/without agmatine (5 or 10 mg/kg/i.p.) was administered to adult male NMRI mice for 5 days. Novel object recognition (NOR) test session was used to assess cognitive function. Following the behavioral assessments, the hippocampi were used to determine the phosphorylated and total levels of GSK-3β and ERK as well as GAPDH using western blot analysis. The results showed that Al-NP impaired NOR memory in mice while agmatine 10 mg/kg prevented the memory deficit induced by Al-NP. Furthermore, Al-NP activated GSK-3β as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3β and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3β and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

Protective Effect of Galantamine against Doxorubicin-Induced Neurotoxicity.

Doxorubicin (DOX) causes cognitive impairment (chemobrain) in patients with cancer. While DOX damages the cholinergic system, few studies have focused on the protective effects of cholinergic function on chemobrain. The acetylcholinesterase inhibitor galantamine (GAL) demonstrates neuroprotective properties. We investigated the mechanisms associated with DOX-induced cognitive impairments and the potential protective role of GAL in preventing chemobrain. Female Wistar rats were divided into control, DOX, GAL, and DOX + GAL groups. The rats in the DOX group were administered DOX (5 mg/kg intraperitoneally twice weekly for two weeks), while those in the GAL group were orally administered GAL (2.5 mg/kg) via oral gavage once daily for 15 days. The combination group (DOX + GAL) received GAL (once daily) and DOX (two times per week) concurrently. The body weights and survival rates were monitored daily. The animals were subjected to behavioral tests to assess the memory function followed by the biochemical estimation of inflammatory markers, including tumor necrosis factor-α (TNF-α), interleukine-1β (IL-1β), and interleukine-6 (IL-6) in rat brain tissue and RT-qPCR. DOX caused a reduction in the body weight and survival rate, which was alleviated by GAL concomitant treatment with DOX (DOX + GAL). These groups had reduced body weights and survival rates. DOX-treated animals exhibited an impairment of short-term spatial working memory, manifested as a behavioral alteration in the Y-maze test, the novel object recognition (NOR) test, and the elevated plus-maze (EPM) test. Concurrent treatment with GAL (DOX + GAL) showed improved memory function, as evidenced by an increase in the number of entries and time spent in the novel arm, the time spent exploring the novel object, and the transfer latency in the Y-maze, NOR test, and EPM test, respectively. These findings were also supported by biochemical observations showing the reversal of DOX-induced changes in IL-1β, IL-6, and TNF-α, as well as their relative expression of mRNA in brain tissue following concurrent GAL treatment. GAL appeared to be a neuroprotective agent against neuroinflammation caused by DOX by reducing inflammatory markers in the brain.

The Ameliorative Effect of Pioglitazone against Neuroinflammation Caused by Doxorubicin in Rats.

Doxorubicin (DOX) is a chemotherapeutic agent that is linked with complications such as cardiotoxicity and cognitive dysfunction, known as chemobrain. Chemobrain affects up to 75% of cancer survivors, and there are no known therapeutic options for its treatment. This study aimed to determine the protective effect of pioglitazone (PIO) against DOX-induced cognitive impairment. Forty Wistar female rats were equally divided into four groups: control, DOX-treated, PIO-treated, and DOX + PIO-treated. DOX was administered at a dose of 5 mg/kg, i.p., twice a week for two weeks (cumulative dose, 20 mg/kg). PIO was dissolved in drinking water at a concentration of 2 mg/kg in the PIO and DOX-PIO groups. The survival rates, change in body weight, and behavioral assessment were performed using Y-maze, novel object recognition (NOR), and elevated plus maze (EPM), followed by estimation of neuroinflammatory cytokines IL-6, IL-1β, and TNF-α in brain homogenate and RT-PCR of a brain sample. Our results showed a survival rate of 40% and 65% in the DOX and DOX + PIO groups, respectively, compared with a 100% survival rate in the control and PIO treatment groups at the end of day 14. There was an insignificant increase in body weight in the PIO group and a significant reduction in the DOX and DOX + PIO groups as compared with the control groups. DOX-treated animals exhibited impairment of cognitive function, and the combination PIO showed reversal of DOX-induced cognitive impairment. This was evidenced by changes in IL-1β, TNF-α, and IL-6 levels and also by mRNA expression of TNF- α, and IL-6. In conclusion, PIO treatment produced a reversal of DOX-induced memory impairment by alleviating neuronal inflammation by modulating the expression of inflammatory cytokines.

Quantitative-HPLC-DAD polyphenols analysis, anxiolytic and cognition enhancing potentials of Sorbaria tomentosa Lindl. Rehder

Ethnopharmacological relevanceMedicinal plants of the family Rosaceae have a long history of traditional uses in the management of neurological disorders. Sorbaria tomentosa Lindl. Rehder is composed of antioxidant and neuroprotective polyphenolics. Aims of the studyThe current study was designed to explore phenolics profile via high performance liquid chromatography-photodiode array detector (HPLC-DAD) and validated the neuroprotective and anxiolytic potentials of S. tomentosa by applying in vitro and in vivo approaches. Materials and methodsThe plant crude methanolic extract (St.Crm) and fractions were subjected to HPLC-DAD analysis for qualitative and quantitative assessment of phytochemicals. Samples were screened for in vitro free radicals scavenging assays by using 2,2-diphenylpicrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) along with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibition assays. For cognitive and anxiolytic studies, mice were subjected to open field, elevated plus maze (EPM), light-dark model, Y-maze, shallow water maze (SWM), and novel object recognition (NOR) tests. ResultsHPLC-DAD analysis revealed the presence of high concentrations of phenolic compounds. For instance, in St.Cr, 21 phenolics were quantified, among which apigenin-7-glucoside (291.6 mg/g), quercetin (122.1 mg/g), quercetin-3-feruloylsophoroside-7-glucoside (52.6 mg/g), quercetin-7-glucoside (51.8 mg/g), ellagic acid (42.7 mg/g), luteolin (45.0 mg/g), kaempferol (40.5 mg/g), 5-feruloylquinic acid (43.7 mg/g) were present in higher concentrations. Likewise, in ethyl acetate fraction (St.Et.Ac), 21 phenolics were identified as 3,5-di-caffeoylquinic acid (177.4 mg/g) and 5-hydroxybenzoylquinic acid (46.9 mg/g) were most abundant phytochemicals. Highly valuable phenolics were also identified in other fractions including butanol (St.Bt), chloroform (St.Chf), and n-hexane (St.Hex). The various fractions exhibited concentration dependent inhibition of free radicals in DPPH and ABTS assays. Potent AChE inhibitory potentials were revealed by the test samples with St.Chf, St.Bt and St.EtAc being the most active having an IC50 of 298.1, 580.1, and 606.47 μg mL−1, respectively. Similarly, St.Chf, St.Bt, St.EtAc and St.Cr exhibited potent BChE inhibitory activity and was observed as 59.14, 54.73, 51.35 and 49.44%, respectively. A significant improvement in the exploratory behavior was observed in open field test and stress/anxiety was relieved effectively at 50-100 mg/kg. Likewise, EPM, light-dark and NOR tests revealed an anxiolytic and memory enhancing behaviors. These effects were further corroborated from the Y-maze and SWM transgenic studies that showed considerable improvement in cognition retention. ConclusionsThese findings concluded that S. tomentosa possessed potential anxiolytic and nootropic efficacies and may have therapeutic potential in neurodegenerative disorders.

Thermal cycling-hyperthermia ameliorates Aβ25-35-induced cognitive impairment in C57BL/6 mice

Despite continuation of some controversies, Alzheimer’s disease (AD), the most common cause of dementia nowadays, has been widely believed to derive mainly from excessive β-amyloid (Aβ) aggregation, that would increase reactive oxygen species (ROS) and induce neuroinflammation, leading to neuron loss and cognitive impairment. Existing drugs on Aβ have been ineffective or offer only temporary relief at best, due to blood–brain barrier or severe side effects. The study employed thermal cycling-hyperthermia (TC-HT) to ease the Aβ-induced cognitive impairments and compared its effect with continuous hyperthermia (HT) in vivo. It established an AD mice model via intracerebroventricular (i.c.v.) injection of Aβ25-35, proving that TC-HT is much more effective in alleviating its performance decline in Y-maze and novel object recognition (NOR) tests, in comparison with HT. In addition, TC-HT also exhibits a better performance in decreasing the hippocampal Aβ and β-secretase (BACE1) expressions as well as the neuroinflammation markers–ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) levels. Furthermore, the study finds that TC-HT can elevate more protein expressions of insulin degrading enzyme (IDE) and antioxidative enzyme superoxide dismutase 2 (SOD2) than HT. In sum, the study proves the potential of TC-HT in AD treatment, which can be put into application with the use of focused ultrasound (FUS).

Cognitive Impairments, Neuroinflammation and Blood-Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation during the Daylight Period.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-brain barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks and in a subset 2 or 6 weeks of normal sleep recovery. The presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation, as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p < 0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patients with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.