Memory Deficits In Rats Research Articles

Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ42 and compared them to those of synthetic Aβ42. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models. Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ42 and Asp7 iso-Aβ42. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module. AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ42 induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide. The findings support the further investigation of Asp7 iso-Aβ42 in translational research on AD and suggest its involvement in neurodegenerative processes.

Pretreatment with Liposome-Encapsulated Shrimp Shell Extract Attenuated Neuronal Damage and Death in Aβ1-42-Induced Memory Deficits in Rats.

The accumulation of amyloid-beta (Aβ) peptides is a crucial factor in the neuronal degeneration of Alzheimer's disease (AD). The current study investigated the underlying neuroprotective mechanisms of shrimp shell extract (SSE) and liposome-encapsulated SSE (SSE/L) against Aβ1-42-induced neuronal damage and death in rats. Intracerebroventricular infusion of Aβ1-42 effectively induced memory decline, as observed in a reduction of the rat's discriminating ability in the novel object recognition and novel object location tasks. Oral pretreatment with 100mg/kg of SSE demonstrated no preventive effect on the memory decline induced by Aβ1-42 infusion. However, treatment with SSE/L 100mg/kg BW effectively attenuated memory deficits in both behavioral assessments following two and four weeks after Aβ1-42 infusion. Moreover, SSE/L exerted neuroprotective effects by reducing lipid peroxidation and increasing Nrf2/HO-1 expression. There was a significant decrease in Iba1 and GFAP (biomarkers of microglia and astrocyte activity, respectively), as well as a decrease in the levels of NF-κB expression and the inflammatory cytokines TNF-α and IL-6 in the cortical and hippocampal tissues. Treatment with SSE/L also reduced the pro-apoptotic proteins Bax and cleaved caspase-3 while raising the anti-apoptotic protein Bcl2. In addition, the beneficial effects of SSE/L were along with the effects of a positive control commercial astaxanthin (AST). The findings of this study indicated that SSE/L provided neuroprotective effects on Aβ1-42-induced AD rats by ameliorating oxidative stress, neuroinflammation and apoptotic cell death. Therefore, SSE/L might be employed to prevent and mitigate Aβ accumulation-induced neurotoxicity in AD.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and β-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease β-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

Scutellaria Baicalensis Georgi Stem and Leaf Flavonoids Ameliorate the Learning and Memory Impairment in Rats Induced by Okadaic Acid.

The objective of this study is to explore the impact and underlying mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on cognitive impairment caused by intracerebroventricular injection of okadaic acid (OA) in rats. An experimental model of Alzheimer's disease (AD) was induced in rats by intracerebroventricular injection of OA, resulting in memory impairment. The Morris water maze test was employed to confirm the successful establishment of the memory impairment model. The rats that exhibited significant memory impairment were randomly divided into different groups, including a model group, three SSFs dose groups (25, 50, and 100 mg/kg), and a positive control group treated with Ginkgo biloba tablets (GLT) at a dose of 200 mg/kg. To evaluate the learning and memory abilities of the rats, the Morris water maze test was conducted. Hematoxylin-eosin (HE) staining was used to observe any morphological changes in neurons. Immunohistochemistry (IHC) was performed to measure the expression of choline acetyltransferase (ChAT) protein. Western blotting (WB) was utilized to assess the phosphorylation levels of tau protein at Ser262 and Ser396. The activities of inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS) were quantified using ultraviolet spectrophotometry. The levels of inflammatory factors, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were measured using ELISA. In rats, the administration of OA via intracerebroventricular injection resulted in cognitive impairment, neuropathological changes, and alterations in protein expression and activity levels. Specifically, the protein expression of ChAT was significantly reduced (P<0.01), while the phosphorylation levels of tau protein at Ser262 and Ser396 were significantly increased (P<0.01). Moreover, iNOS activity in the hippocampus and cerebral cortex exhibited a significant increase (P<0.01), whereas cNOS activity showed a decrease (P<0.05). Furthermore, the levels of IL-1β and TNF-α in the cerebral cortex were elevated (P<0.01), while the level of IL-6 was decreased (P<0.05). The administration of three doses of SSFs and GLT to rats exhibited varying degrees of improvement in the aforementioned pathological alterations induced by OA. SSFs demonstrated the ability to enhance cognitive function and mitigate memory deficits in rats following intracerebroventricular injection of OA. This beneficial effect may be attributed to the modulation of ChAT protein expression, tau hyperphosphorylation, NOS activity, and inflammatory cytokine levels by SSFs.

Neuro-protective Effect of Acetyl-11-keto-β-boswellic Acid in a Rat Model of Scopolamine-induced Cholinergic Dysfunction.

Acetyl-11-keto-β-boswellic acid (AKBA) is a major component of the oleo-gum resin of B. serrata with multiple pharmacological activities. The objective of this study was to explore the underlying mechanisms of neuroprotective potential of AKBA against scopolamine-mediated cholinergic dysfunction and memory deficits in rats. The rats received AKBA (2.5, 5, and 10 mg/kg, oral) for 21 days. In the third week, scopolamine was administered 30 min before the Morris water maze and passive avoidance tests. In order to perform biochemical assessments, the hippocampus and prefrontal cortex were extracted from the rats euthanized under deep anesthesia. In the MWM test, treatment with AKBA (5 and 10 mg/kg) decreased the latency and distance to find the platform. Moreover, in the PA test, AKBA remarkably increased latency to darkness and stayed time in lightness while decreasing the frequency of entry and time in the darkness. According to the biochemical assessments, AKBA decreased acetylcholinesterase activity and malondialdehyde levels while increasing antioxidant enzymes and total thiol content. Furthermore, AKBA administration restored the hippocampal mRNA and protein levels of brain-derived neurotrophic factor (BDNF) and mRNA expression of B-cell lymphoma (Bcl)- 2 and Bcl-2- associated X genes in brain tissue of scopolamine-injured rats. The results suggested the effectiveness of AKBA in preventing learning and memory dysfunction induced by scopolamine. Accordingly, these protective effects might be produced by modulating BDNF, cholinergic system function, oxidative stress, and apoptotic markers.

Icariin rescues developmental BPA exposure induced spatial memory deficits in rats

Bisphenol A (BPA) has been implicated in cognitive impairment. Icariin is the main active ingredient extracted from Epimedium Herb with protective function of nervous system. However, the potential therapeutic effects of Icariin on spatial memory deficits induced by developmental BPA exposure in Sprague-Dawley rats have not been investigated. This study investigated the therapeutic effect of Icariin (10 mg/kg/day, from postnatal day (PND) 21 to PND 60 by gavage) on spatial memory deficits in rat induced by developmental BPA exposure (1 mg/kg/day, from embryonic to PND 60), demonstrating that Icariin can markedly improve spatial memory in BPA-exposed rat. Furthermore, intra-gastric administration of Icariin could attenuate abnormal hippocampal cell dispersion and loss, improved the dendritic spine density and Nissl bodies. Moreover, Icariin reversed BPA induced reduction of frequency of miniature excitatory postsynaptic currents(mEPSC) and decrease of Vesicular glutamate transporter 1(VGlut1). Collectively, Icariin could effectively rescue BPA-induced spatial memory impairment in male rats by preventing cell loss and reduction of dendritic spines in the hippocampus. In addition, we also found that VGlut1 is a critical target in the repair of BPA-induced spatial memory by Icariin. Thus, Icariin may be a promising therapeutic agent to attenuate BPA-induced spatial memory deficits.

Restoring Synaptic Function: How Intranasal Delivery of 3D-Cultured hUSSC Exosomes Improve Learning and Memory Deficits in Alzheimer's Disease.

Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD.

Mice deficient in complement C3 are protected against recognition memory deficits and astrogliosis induced by status epilepticus.

Status epilepticus (SE) can significantly increase the risk of temporal lobe epilepsy (TLE) and cognitive comorbidities. A potential candidate mechanism underlying memory defects in epilepsy may be the immune complement system. The complement cascade, part of the innate immune system, modulates inflammatory and phagocytosis signaling, and has been shown to contribute to learning and memory dysfunctions in neurodegenerative disorders. We previously reported that complement C3 is elevated in brain biopsies from human drug-resistant epilepsy and in experimental rodent models. We also found that SE-induced increases in hippocampal C3 levels paralleled the development of hippocampal-dependent spatial learning and memory deficits in rats. Thus, we hypothesized that SE-induced C3 activation contributes to this pathophysiology in a mouse model of SE and acquired TLE. In this study C3 knockout (KO) and wild type (WT) mice were subjected to one hour of pilocarpine-induced SE or sham conditions (control; C). Following a latent period of two weeks, recognition memory was assessed utilizing the novel object recognition (NOR) test. Western blotting was utilized to determine the protein levels of C3 in hippocampal lysates. In addition, we assessed the protein levels and distribution of the astrocyte marker glial fibrillary acidic protein (GFAP). In the NOR test, control WT + C or C3 KO + C mice spent significantly more time exploring the novel object compared to the familiar object. In contrast, WT+SE mice did not show preference for either object, indicating a memory defect. This deficit was prevented in C3 KO + SE mice, which performed similarly to controls. In addition, we found that SE triggered significant increases in the protein levels of GFAP in hippocampi of WT mice but not in C3 KO mice. These findings suggest that ablation of C3 prevents SE-induced recognition memory deficits and that a C3-astrocyte interplay may play a role. Therefore, it is possible that enhanced C3 signaling contributes to SE-associated cognitive decline during epileptogenesis and may serve as a potential therapeutic target for treating cognitive comorbidities in acquired TLE.

Investigation of the Asyogh's rectangular device for learning and memory testing in Wistar rats.

This study aimed to design Asyogh's rectangular device that is used for memory testing in rodents. It was found that scopolamine (3 mg/kg i.p.) and diazepam (1 mg/kg i.p.) caused significant memory deficits in rats, as evidenced by increased transfer latency times. However, these memory deficits were significantly reversed when the rats were pretreated with Donepezil. It further demonstrates that pretreated donepezil is able to effectively restore the memory deficits induced by scopolamine and diazepam, as indicated by the significant recovery in TLT. The present study showed that the device used to measure transfer latency time that was a valuable tool for assessing memory and cognitive function in rodents.

Co-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development

Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.

Impaired Lactate Release in Dorsal CA1 Astrocytes Contributed to Nociceptive Sensitization and Comorbid Memory Deficits in Rodents.

Memory deficits are a common comorbid disorder in patients suffering from neuropathic pain. The mechanisms underlying the comorbidities remain elusive. The hypothesis of this study was that impaired lactate release from dysfunctional astrocytes in dorsal hippocampal CA1 contributed to memory deficits. A spared nerve injury model was established to induce both pain and memory deficits in rats and mice of both sexes. von Frey tests, novel object recognition, and conditioned place preference tests were applied to evaluate the behaviors. Whole-cell recording, fiber photometry, Western blotting, and immunohistochemistry combined with intracranial injections were used to explore the underlying mechanisms. Animals with spared sciatic nerve injury that had displayed nociception sensitization or memory deficit comorbidities demonstrated a reduction in the intrinsic excitability of pyramidal neurons, accompanied by reduced Ca2+ activation in astrocytes (ΔF/F, sham: 6 ± 2%; comorbidity: 2 ± 0.4%) and a decrease in the expression of glial fibrillary acidic protein and lactate levels in the dorsal CA1. Exogenous lactate supply or increasing endogenous lactate release by chemogenetic activation of astrocytes alleviated this comorbidity by enhancing the cell excitability (129 ± 4 vs. 88 ± 10 for 3.5 mM lactate) and potentiating N-methyl-d-aspartate receptor-mediated excitatory postsynaptic potentials of pyramidal neurons. In contrast, inhibition of lactate synthesis, blocking lactate transporters, or chemogenetic inhibition of astrocytes resulted in comorbidity-like behaviors in naive animals. Notably, β2-adrenergic receptors in astrocytes but not neurons were downregulated in dorsal CA1 after spared nerve injury. Microinjection of a β2 receptor agonist into dorsal CA1 or activation of the noradrenergic projections onto the hippocampus from the locus coeruleus alleviated the comorbidity, possibly by increasing lactate release. Impaired lactate release from dysfunctional astrocytes, which could be rescued by activation of the locus coeruleus, led to nociception and memory deficits after peripheral nerve injury.

Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.

To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and Baihui (GV20) and Sanyinjiao (SP6) on the PKA/CREB and BDNF/TrkB signaling, as well as neuroapoptosis and neurogenesis in hippocampus and elucidate the underlying mechanism of single and combined acupoints on ameliorating spatial learning and memory deficits in a rat model of primary insomnia. Primary insomnia was modeled by intraperitoneal injection of para-chlorophenylalanine (PCPA) once daily for 2 d. EA was applied at Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), or Shenmen (HT7) + Baihui (GV20) + Sanyinjiao (SP6) (combined) for 30 min daily for 4 d. Spatial learning and memory function was evaluated by the Morris water maze (MWM) test. Protein expressions of hippocampal cAMP-dependent protein kinase (PKA)-Cβ, phosphorylated cAMP-responsive element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) were evaluated by Western blotting. Neuronal apoptosis in the hippocampus was detected with the transferase-mediated dUTP-X nick end labeling assay. Endogenous neurogenesis was examined with bromodeoxyuridine staining. The MWM test and hippocampal p-CREB, BDNF, and TrkB protein levels in the combined acupoints group were evaluated after the administration of a PKA-selective inhibitor (H89). Spatial learning and memory were significantly impaired in rats with insomnia. The spatial learning deficits were ameliorated in the Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), and combined groups; this improvement was significantly greater in the combined group than the single acupoint groups. The spatial memory impairment was improved in the combined, Baihui (GV20), and Shenmen (HT7) groups, but not the Sanyinjiao (SP6) group. The expressions of PKA-Cβ, p-CREB, BDNF, and TrkB were decreased in rats with insomnia. All these proteins were significantly upregulated in the combined group. PKA/p-CREB protein levels were elevated in the Baihui (GV20) and Shenmen (HT7) groups, whereas BDNF/TrkB expression was upregulated in the Sanyinjiao (SP6) group. The staining results showed significant attenuation of hippocampal cell apoptosis and increased numbers of proliferating cells in the combined group, whereas the single acupoint groups only showed decreased numbers of apoptotic cells. In the combined group, the PKA inhibitor reversed the improvement of spatial memory and upregulation of p-CREB expression caused by EA, but did not affect its activation of BDNF/TrkB signaling. EA at the single acupoints Baihui (GV20), Shenmen (HT7), or Sanyinjiao (SP6) had an ameliorating effect on the spatial learning and memory deficits induced by insomnia. EA at combined acupoints exerted a synergistic effect on the improvements in spatial learning and memory impairment in rats with insomnia by upregulating the hippocampal PKA/CREB and BDNF/TrkB signaling, facilitating neurogenesis, and inhibiting neuronal apoptosis. These findings indicate that EA at combined acupoints [(Baihui (GV20), Shenmen (HT7), and Sanyinjiao (SP6)] achieves a more pronounced regulation of hippocampal neuroplasticity than EA at single acupoints, which may partly explain the underlying mechanisms by which EA at combined acupoints exerts a better ameliorative effect on the cognitive dysfunction caused by insomnia.

Erucic acid ameliorates the lipopolysaccharide‐induced memory deficit in rats through inhibited inflammation cytokines expression/caspase 3/NF‐κB pathways

AbstractErucic acid is a single unsaturated fatty acid that falls under the omega‐9 fatty acid family. It was suggested to treat Wistar rats with lipopolysaccharide (LPS)‐induced memory impairment and minimize cognitive impairment. A total of 30 animals were randomized: group I was normally treated group, group II was administered with LPS, group III was treated with LPS along with erucic acid at the dose of 10 mg kg–1 p.o.–1, group IV was treated with LPS along with erucic acid at 20 mg kg–1 p.o.–1 and group V was the erucic acid per se group provided at the dose of 20 mg kg–1 p.o.–1 per se. Behavioral tests were evaluated by using the Morris water maze and Y‐maze. Biochemical analysis including acetylcholine esterase (AChE), choline acetyltransferase (ChAT), glutathione (GSH), catalase activity (CAT), superoxide dismutase (SOD), and nitric oxide (NO) along with proinflammatory mediators tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), caspase 3, and neuroinflammatory biomarker (nuclear factor kappa B‐NF‐κB) were measured. Erucic acid produced substantial behavioral improvement in the Y‐maze test, including spontaneous alterations and reduced latency time during acquisition, and a longer duration of time in the consolidation phase undergoing the MWM test. Furthermore, erucic acid improved the AChE, proinflammatory markers, and oxidative stress as well as restoring endogenous antioxidant levels, ChAT, caspase 3, and NF‐κB levels. Erucic acid may be a therapeutic component for conditions related to memory disorders such as memory impairment, enhances memory functioning, and protects against neuronal damage.

Decreased expression of Chrna4 by METTL3-mediated m6A modification participates in BPA-induced spatial memory deficit

Bisphenol A (BPA), a widely used endocrine disruptor, has been implicated in cognitive impairment via epigenetic machinery. N6-methyl adenosine (m6A) has recently emerged as a new epigenetic factor that influences cognition, but the role of m6A in BPA induced cognitive deficits has not been explored yet. In this study, we found increased global m6A abundance accompanied with elevated expression of methyltransferase-like 3 (METTL3) in hippocampal neurons following BPA exposure. Inhibition of METTL3 activity by selective METTL3 inhibitor 2457 (STM) in cultured neurons abolished BPA induced m6A upregulation and abnormal synaptic transmission. Additionally, knockdown of METTL3 in hippocampus abrogated BPA induced learning and memory deficit in rats. Further study showed that m6A modification was enriched in mRNA of cholinergic receptor nicotinic alpha 4 subunit (Chrna4). Inhibition of METTL3 either by STM or shRNA restored BPA induced downregulation of Chrna4, suggesting that Chrna4 may be a potential target involved in BPA induced neurotoxicity that modified by m6A. Collectively, our findings demonstrated that METTL3 mediated m6A modification was involved in BPA induced cognitive deficit with Chrna4 as a potential target, which enriched our understanding of the role of epigenetics (RNA modifications) in BPA induced neurotoxicity and provided new insights into BPA or its substitutes induced damages in other organs.

Neuroprotective Effects of Ocimum basilicum L. var. thyrsiflora on Scopolamine-Induced Non-Spatial Memory Deficits in Rats

Pharmacological studies indicated that Ocimum basilicum L. var. thyrsiflora has numerous therapeutic potentials. The aim of this study was to investigate the neuroprotective action of O. basilicum leaf extract against scopolamine-induced non-spatial memory deficits in rats and to determine the changes in mRNA expressions of genes implicated in cognition and neuroprotection. O. basilicum leaves were extracted with 80% ethanol and verified for the presence of rosmarinic acid using high performance liquid chromatography method. Male Wistar rats were treated orally with either O. basilicum or the positive control piracetam for 14 days prior to the injection of 0.5 mg/kg scopolamine on the day of the novel object discrimination (NOD) test. Hippocampi were collected at the end of the test. mRNA expression of nicotinic acetylcholine α7 subunit (NA7), muscarinic M1 receptor (M1), neuronal nitric oxide synthase (nNOS), and 5-hydroxytryptamine receptor 3A (HTR3A) genes in the hippocampi were analyzed using qPCR method. The presence of rosmarinic acid in the plant extract was detected at chromatogram peak of Rt=16.891. NOD test results indicated that the lower dose of O. basilicum (200 mg/kg) significantly (p&lt;0.05) reversed scopolamine-induced memory deficits in rats similar to the effects of piracetam. In addition, O. basilicum at the same dose alleviated the increase in mRNA expressions of the NA7, M1, nNOS, and HTR3A genes induced by scopolamine. The present findings suggest that O. basilicum is potentially neuroprotective in preventing memory impairment through alleviation of scopolamine-induced changes in hippocampal mRNA expression implicated in cognition and neuroprotection.

Krill Oil attenuates doxorubicin induced cognitive impairment by inhibiting oxidative stress markers in the brains of wistar rats

Chemobrain is a typical adverse effect of chemotherapeutics agents that affects 15–80 percent of cancer patients. Doxorubicin, an antineoplastic drug, has been associated with severe neurotoxicity manifested as a loss in cognitive skills, most likely due to oxidative stress in brain. Krill oil (KO) is a unique, naturally occurring nutrient derived from a type of Antarctic krill, Euphausia superba that is commonly used as a dietary supplement and is well known for anti-inflammatory, hypolipidemic, anti-depressant and improvement of cognitive function, protection of neurodegeneration, neuroprotective and antioxidant qualities. The current study was aimed at evaluating krill oil's potential neuroprotection and memory improving benefits against Doxorubicin-induced cognitive and neurobiological defects. A novel object recognition task and Morris water maze test were conducted to evaluate the protective effect of krill oil against doxorubicin-induced memory deficits in rats. In female Wistar rats, cognitive impairment was produced by administering ten cycles of Doxorubicin (2.5mg/kg, intra peritoneal, once every five days). Krill oil (50mg/kg and 100mg/kg) was given orally starting one week prior to the doxorubicin treatment and continued throughout the study. Krill treatment (50mg/kg and 100mg/kg) significantly protected against Doxorubicin induced memory impairment. Co-administration of both doses of krill oil resulted in significantly lower the levels of tumour necrosis factor (TNFα), and acetyl cholinesterase activity. Furthermore, doxorubicin-induced oxidative and inflammatory insults in the frontal cortex and hippocampal areas of the brain were prevented by krill oil. In conclusion, krill oil may be a promising adjuvant treatment option for reducing adverse effects associated to doxorubicin treatment.

Hibiscus sabdariffa synthesized gold nanoparticles ameliorate aluminum chloride induced memory deficits through inhibition of COX-2/BACE-1 mRNA expression in rats

Alzheimer’s disease (AD) is a major health challenge worldwide, especially among the elderly. The disease is associated with cognitive and memory deficits. This study investigated the effect of Hibiscus sabdariffa synthesized-gold nanoparticles (HS-AuNPs) on AlCl3-induced memory deficits in rats. Forty-two male Wistar rats were divided into six groups (n = 7). Group I served as control. Rats in group II - V were exposed to AlCl3 (100 mg/kg) to induce AD. Group III - V rats were treated with 5 mg/kg donepezil, 5 and 10 mg/kg HS-AuNPs, respectively, for 14 days. Behavioral tests were carried out on the rats on day 28 and 42. At the end of animal experiment, rats were sacrificed and used for various biochemical assays and gene expression. The AD rats showed memory and learning impairment, and these conditions were ameliorated by HS-AuNPs. Significant (p < 0.05) elevation in the activities of acetylcholinesterase, monoamine oxidase and adenosine deaminase, as well as malondialdehyde levels was noted. A significant reduction in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) noted in AlCl3-induced rats were ameliorated by the 5 and 10 mg/kg b.w. doses of HS-AuNPs. In addition, the increased mRNA expression of cyclooxygenase-2 (COX-2) and beta-secretase 1 (BACE-1) caused by AlCl3 were assuaged by the HS-AuNPs treatment. Based on the activities of HS-AuNPs against AlCl3-induced AD, HS-AuNPs could be considered a potential therapeutic agent for managing AD.

Neuroprotective Role of Esculetin, A Coumarin Derivative Against Aluminium Chloride Induced Cognitive Deficits in Rats

Esculetin, a hydroxycoumarin, has been reported to have neuroprotective action against several neurotoxins. Aluminum, a nonessential element and potent neurotoxin, has been suggested to have a link with the etiology and progression of Alzheimer's disease (AD). In this experiment, the possible neuroprotective role of esculetin on aluminium chloride mediated cognitive impairments in rats was investigated. Rats were orally treated with aluminum chloride (100mg/kg/day) and esculetin (25 and 50mg/kg/day) for 42 days. Cognitive functions were analysed by performing several behavioural tests: Passive avoidance test, Morris water maze test, modified elevated plus maze test, radial arm maze, and open field test. The results of the present study indicated that esculetin attenuated aluminum-induced memory deficits in rats. Therapeutic approaches for AD mainly target the inhibition of acetylcholine esterase, thereby preventing the damage of acetyl choline and improving the cholinergic transmission in the CNS. Previous studies demonstrated the potent AChE inhibitory activity of esculetin may be due to the presence of hydroxyl groups (6, 7, or 8 positions) and o-dihydroxyl (catechol) group. Hence, the AChE inhibition property of esculetin may be responsible for its memory enhancing activity. Key words - Alzheimer’s disease, aluminium, esculetin, memory, locomotion.

Sex-Dependent Effect of Chronic Piromelatine Treatment on Prenatal Stress-Induced Memory Deficits in Rats.

Prenatal stress impairs cognitive function in rats, while Piromelatine treatment corrects memory decline in male rats with chronic mild stress. In the present study, we aimed to evaluate the effect of chronic treatment with the melatonin analogue Piromelatine on the associative and spatial hippocampus-dependent memory of male and female offspring with a history of prenatal stress (PNS). We report that male and female young adult offspring with PNS treated with a vehicle had reduced memory responses in an object recognition test (ORT). However, the cognitive performance in the radial arm maze test (RAM) was worsened only in the male offspring. The 32-day treatment with Piromelatine (20 mg/kg, i.p.) of male and female offspring with PNS attenuated the impaired responses in the ORT task. Furthermore, the melatonin analogue corrected the disturbed spatial memory in the male offspring. While the ratio of phosphorylated and nonphosphorylated adenosine monophosphate response element binding protein (pCREB/CREB) was reduced in the two sexes with PNS and treated with a vehicle, the melatonin analogue elevated the ratio of these signaling molecules in the hippocampus of the male rats only. Our results suggest that Piromelatine exerts a beneficial effect on PNS-induced spatial memory impairment in a sex-dependent manner that might be mediated via the pCREB/CREB pathway.

Development of stable, orally bioavailable small molecule positive modulators of HGF/MET signaling for the treatment of cognitive impairment.

AbstractBackgroundPositive modulators of the HGF/MET system likely represent a valuable therapeutic class with the potential to impact a variety of disorders, including neurodegenerative diseases and indications with cognitive impairment. Preclinical and clinical studies have established the therapeutic potential of fosgonimeton (ATH‐1017), a small molecule injectable positive modulator of the HGF/MET system that is currently in clinical trials in patients with Alzheimer’s disease and Parkinson’s disease. At Athira Pharma, Inc., we have worked to expand the platform of HGF/MET positive modulators by identifying small molecules with a range of properties with the potential to meet therapeutic and delivery needs of patients across neurological diseases.MethodBuilding on the MET receptor augmentation activity of fosgonimeton, we designed a screening funnel to evaluate chemical variants with desired physiochemical properties. We synthesized a panel of small molecules intended to promote pharmacokinetic stability and tested each variant for in vitro activity via MET phosphorylation. Active molecules were then tested for in vitro stability, in vivo pharmacokinetics, and in vivo efficacy in a scopolamine‐induced spatial memory test.ResultWe identified a panel of molecules with novel chemistry, biochemical activity in vitro, and favorable physiochemical properties. Among these active molecules, several were selected to move into advanced testing. In pharmacokinetic evaluation, these molecules efficiently distributed to the brain and other target tissues following oral administration. Selected molecules were advanced to in vivo efficacy testing, which resulted in reversal of scopolamine‐induced spatial memory deficits in rats as assessed in the Morris water maze.ConclusionNovel, stabilized small molecule positive modulators of HGF/MET demonstrated procognitive effects following oral delivery. Further development of these compounds may have the potential to provide an array of administration options for patients with neurodegenerative or cognitive disorders.