Cognitive Impairment In Animal Model Research Articles

Effects of Microplastics on Mental Health

The impact of microplastics on mental health is an emerging area of research, and the medical literature points to potential neurobehavioral effects. Studies have shown that exposure to microplastics can lead to changes in behavior, neurotoxicity, and cognitive impairments in animal models. Although these findings from animal studies suggest a possible link between microplastic exposure and mental health outcomes, it is important to note that research in this area is still limited and more studies are needed to understand the mechanisms and consequences for human health.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Deciphering Neuroprotective Effect of Rosmarinus officinalis L. (syn. Salvia rosmarinus Spenn.) through Preclinical and Clinical Studies.

Rosmarinus officinalis L. (RO, rosemary) is a well-known medicinal, aromatic, and culinary herb with traditional use in European folk medicine against memory deficits and neurodegenerative disorders. This review highlights the different neuroprotective activities of RO investigated in both preclinical and clinical studies, as well as in silico molecular docking of bioactive compounds found in RO. The neuroprotective effect of RO was searched through databases including PubMed, Web of Science (WoS), Scopus, and Clinical Trials using the keywords "Rosmarinus officinalis, rosemary, neuroprotective effect, memory, cognitive dysfunction, Alzheimer's disease." RO, which is rich in secondary metabolites that have memory-enhancing potential, has displayed neuroprotection through different molecular mechanisms such as inhibition of cholinesterase, modulation of dopaminergic and oxytocinergic systems, mediation of oxidative and inflammatory proteins, involved in neuropathic pain, among others. RO extracts exhibited antidepressant and anxiolytic activities. Also, the plant has shown efficacy in scopolamine-, lipopolysaccharide-, AlCl3 -, and H2O2 -induced amnesia as well as amyloid-beta- and ibotenic acid-induced neurotoxicity and chronic constriction injury-related oxidative stress memory and cognitive impairments in animal models. A few clinical studies available supported the neuroprotective effects of RO and its constituents. However, more clinical studies are needed to confirm results from preclinical studies further and should include not only placebo-controlled studies but also studies including positive controls using approved drugs. Many studies underlined that constituents of RO may have the potential for developing drug candidates against Alzheimer's disease that possess high bioavailability, low toxicity, and enhanced penetration to CNS, as revealed from the experimental and molecular docking analysis.

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway.

Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

Is adiponectin deficiency a critical factor for sevoflurane induced neurocognitive dysfunction?

The global rise in obesity has resulted in an increase in the number of surgical procedures under general anaesthesia in this patient population. Sevoflurane is one of the most widely used volatile aesthetic agent in developed countries. Clinical evidence suggests obesity is a risk factor for cognitive dysfunction after surgery. Experimentally animals with pre-existing cerebral insults are more susceptible to the neurotoxic effects of sevoflurane compared with their normal counterparts. Nevertheless, the mechanism underlying this vulnerability in obese subjects is not fully elucidated.Obesity is associated with a significant reduction of adiponectin, an adipocyte-derived molecule with neurotrophic and anti-inflammatory properties. Adiponectin receptors are abundantly expressed in hippocampus and cortex. Moreover, adiponectin deficiency is associated with exacerbation of neuroinflammation, neuronal dysfunction and cognitive impairment in animal models of obesity and Alzheimer’s disease. Based on these observations, we hypothesize that adiponectin deficiency plays a critical role in sevoflurane induced cognitive dysfunction in obese subjects accounting for its higher incidence in this patient population. With diminished protective effects from adiponectin, sevoflurane may further exacerbate neuroinflammation by activating the proinflammatory pathways and increase the synthesis of inflammatory cytokines in the brain, leading to significant neuronal dysfunction and cognitive impairment. On the other hand, treatment with adiponectin or adiponectin receptor agonists may have therapeutic potential in minimizing the risk of postoperative cognitive impairment in obese patients undergoing surgery. As an oral adiponectin agonist is available, it can be expeditiously evaluated in clinical trials if our hypothesis is validated.

Systematic review and meta-analysis of the effects of exercise on cognitive impairment and neuroprotective mechanisms in diabetes mellitus animal models.

This study aims to assess the effects of exercise on cognitive impairment behavioral performance and neuroprotective mechanisms in diabetes mellitus (DM) animal models. PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database (VIP), and China Biomedical Literature Database (CBM) were systematically searched for studies investigating the impact of exercise on cognitive impairment in animal models of diabetes mellitus (DM) from the inception of these databases through July 2023. Rigorous quality assessments were conducted on the included literature. Primary outcome measures comprised fasting blood glucose (FBG) levels and performance in the Morris water maze test, while secondary outcomes focused on mechanisms related to neuroprotection. Statistical analysis of outcome data was conducted using RevMan 5.3 and R software. A total of 17 studies were included, encompassing 399 animals. The results of the meta-analysis of primary outcome measures revealed that, compared to the control group, exercise effectively reduced fasting blood glucose (FBG) levels in diabetic animal models. In the Morris water maze experiment, exercise also significantly decreased the escape latency of diabetic animal models, increased the number of platform crossings, improved the percentage of time spent in the target quadrant, extended the time spent in the target quadrant, and enhanced swimming speed. Meta-analysis of secondary outcome measures indicated that exercise effectively reduced Aβ deposition, attenuated oxidative stress, enhanced synaptic function, suppressed cellular apoptosis and neuroinflammation, and promoted neurogenesis. Exercise represents a promising non-pharmacological therapy with a positive impact on diabetes-related cognitive function and neuroprotection. Moreover, this study provides a theoretical foundation for further preclinical and clinical trials.

Review of Plant Extracts and Active Components: Mechanisms of Action for the Treatment of Obesity-Induced Cognitive Impairment

Obesity has been shown to negatively impact cognitive functions, but effective treatments for obesity-induced cognitive impairment are lacking. Natural dietary and plant products, functional foods, and plant-derived compounds have gained attention as potential remedies in part due to the nootropic properties of plants and certain plant-derived agents. This review discusses plant extracts and plant-derived substances that have been shown to ameliorate obesity-induced cognitive impairment in animal models. Mechanistic evaluations of their therapeutic effects are also summarized. A literature search was conducted using PubMed and Google Scholar databases, resulting in the review of 27 English language articles meeting the inclusion criteria. The nine plants (e.g., Ashwagandha, Adzuki bean, and olive) and 18 plant-derived substances (e.g., curcumin, Huperzine A, and Roxburgh’s jewel orchid polysaccharides) included in this review improved obesity-induced cognitive impairment through several mechanisms, including attenuation of neuroinflammation, improvement in both central and peripheral insulin resistance, enhancement of neuroprotection and neurogenesis, and modulation of the synthesis and release of cognition-associated neurotransmitters. Based on these findings, plants and plant-derived substances may hold promise for the prevention and treatment of obesity-induced cognitive impairment. Further research is warranted to explore the clinical potential of these plant-derived treatments and to elucidate their underlying molecular mechanisms.

Effect of Curcumin and Coenzyme Q10 Alone and in Combination on Learning and Memory in an Animal Model of Alzheimer's Disease.

The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer's disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study's goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer's disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer's disease and can be utilised alone or as an add-on therapy for the condition.

Literature review on the interdisciplinary biomarkers of multi-target and multi-time herbal medicine therapy to modulate peripheral systems in cognitive impairment.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aβ) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aβ clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD.

Minocycline treatment improves cognitive and functional plasticity in a preclinical mouse model of major depressive disorder

Major depressive disorder (MDD) is a chronic, recurring, and potentially life-threatening illness, which affects over 300 million people worldwide. MDD affects not only the emotional and social domains but also cognition. However, the currently available treatments targeting cognitive deficits in MDD are limited. Minocycline, an antibiotic with anti-inflammatory properties recently identified as a potential antidepressant, has been shown to attenuate learning and memory deficits in animal models of cognitive impairment. Here, we explored whether minocycline recovers the deficits in cognition in a mouse model of depression. C57BL6/J adult male mice were exposed to two weeks of chronic unpredictable mild stress to induce a depressive-like phenotype. Immediately afterward, mice received either vehicle or minocycline for three weeks in standard housing conditions. We measured anhedonia as a depressive-like response, and place learning to assess cognitive abilities. We also recorded long-term potentiation (LTP) as an index of hippocampal functional plasticity and ran immunohistochemical assays to assess microglial proportion and morphology. After one week of treatment, cognitive performance in the place learning test was significantly improved by minocycline, as treated mice displayed a higher number of correct responses when learning novel spatial configurations. Accordingly, minocycline-treated mice displayed higher LTP compared to controls. However, after three weeks of treatment, no difference between treated and control animals was found for behavior, neural plasticity, and microglial properties, suggesting that minocycline has a fast but short effect on cognition, without lasting effects on microglia. These findings together support the usefulness of minocycline as a potential treatment for cognitive impairment associated with MDD.

Modulation of NMDA receptor activity by CR4056, an imidazoline-2 receptor ligand with analgesic properties.

CR4056 is an imidazoline-2 receptor ligand having potent analgesic activity and synergistic effect with opioids. Very recently it has been found that CR4056 can revert the cognitive impairment in animal models of Alzheimer's disease (AD). Since several lines of evidence highlight the importance of NMDAR modulators in nociceptive signaling and in AD progression, we considered as important to investigate the effects of CR4056 on NMDAR activity. In primary culture of cortical neurons, application of NMDA and glycine elicits a current that is decreased in a dose-dependent fashion by CR4056 (IC50 5.3 ± 0.1 µM). CR4056 antagonism is reversible, not competitive and voltage-independent and it is not blocked by pertussis toxin. CR4056 interacts with the co-agonist glycine site in a competitive way, indeed high glycine concentrations diminish its effect. Fibroblasts expressing different recombinant NMDA receptors are differently modulated by CR4056: the potency and the efficacy of the compound are higher in GluN1- GluN2B than in GluN1-GluN2A containing receptors. In lamina II neurons of spinal cord slices, single stimulation of afferent fibers evokes an NMDA-mediated current that is inhibited by 10 µM CR4056. Repetitive stimulation of the dorsal root at high frequency and high intensity produces a firing activity that is significatively depressed by CR4056. Taken together, our results broad the understanding of the molecular mechanisms of CR4056 analgesic activity, involving the modulation of NMDAR activity. Therefore, we propose that the analgesic action of CR4056 and the neuroprotective effects in AD models may be mediated also by NMDAR inhibition.

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.MethodsWe evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.Results Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03–0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.ConclusionsASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators.

The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues. Relocation of the oxo acceptor function and subsequent modulation of the physicochemical properties resulted in novel 1,6-naphthyridines with improved profile, combining good potency, selectivity, ADME, and safety properties. Besides this, compound 20, having the most balanced profile, provided in vivo proof of concept (POC) for the new scaffold in two animal models of cognitive impairment associated with schizophrenia (CIAS).

Carnosine Improves Cognitive Impairment Through Promoting SIRT6 Expression and Inhibiting Endoplasmic Reticulum Stress in a Diabetic Encephalopathy Model.

Diabetic encephalopathy (DE) is one of complications of diabetes mellitus. Carnosine is a dipeptide composed of β-alanine and l-histidine. Study has shown that carnosine could ameliorate cognitive impairment in animal model with diabetes mellitus. However, the mechanism remains unclear. An animal model of type 2 diabetes (db/db mice) was used in this study. The animals were treated with 0.9% saline or carnosine (100 mg/kg) for 8 weeks. Morris water maze was tested after drug administration. Oxidative stress-related factors malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and pro-inflammatory factors inducible nitric oxide synthase (iNOS) were measured. Synapse-related protein postsynaptic density 95 (PSD95) and brain-derived neurotrophic factor (BDNF) were detected by western blot. Besides, the expressions of sirtuin 6 (SIRT6), binding immunoglobulin protein (BIP), protein kinase R-like endoplasmic reticulum kinase (PERK), phospho-protein kinase R-like endoplasmic reticulum kinase (P-PERK), inositol-requiring enzyme-1α (IRE1α), phospho-inositol-requiring enzyme-1α (P-IRE1α), activating transcription factor 6 (ATF6), and C/EBP-homologous protein (CHOP) in the hippocampus of the brain were detected. The results showed that treatment with carnosine ameliorated cognitive impairment in db/db mice. Carnosine reduced neuronal oxidative stress damage and iNOS expression in db/db mice. Meanwhile, carnosine relieved neurodegeneration in the hippocampus of db/db mice. Furthermore, carnosine promoted the expression of SIRT6 and reduced the expressions of endoplasmic reticulum (ER)-related factors (BIP, P-PERK, P-IRE1α, ATF6, and CHOP). In conclusion, these data suggested that the protective effect of carnosine against DE might be related to SIRT6/ER stress pathway.

Magnetic Resonance Imaging in Tauopathy Animal Models.

The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer’s disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models.

Intracellular and extracelluar cyclic GMP in the brain and the hippocampus.

Cyclic Guanosine-Monophosphate (cGMP) is implicated as second messenger in a plethora of pathways and its effects are executed mainly by cGMP-dependent protein kinases (PKG). It is involved in both peripheral (cardiovascular regulation, intestinal secretion, phototransduction, etc.) and brain (hippocampal synaptic plasticity, neuroinflammation, cognitive function, etc.) processes. Stimulation of hippocampal cGMP signaling have been proved to be beneficial in animal models of aging, Alzheimer's disease or hepatic encephalopathy, restoring different cognitive functions such as passive avoidance, object recognition or spatial memory. However, even when some inhibitors of cGMP-degrading enzymes (PDEs) are already used against peripheral pathologies, their utility as neurological treatments is still under clinical investigation. Additionally, it has been demonstrated a list of cGMP roles as not second but first messenger. The role of extracellular cGMP has been specially studied in hippocampal function and cognitive impairment in animal models and it has emerged as an important modulator of neuroinflammation-mediated cognitive alterations and hippocampal synaptic plasticity malfunction. Specifically, it has been demonstrated that extracellular cGMP decreases hippocampal IL-1β levels restoring membrane expression of glutamate receptors in the hippocampus and cognitive function in hyperammonemic rats. The mechanisms implicated are still unclear and might involve complex interactions between hippocampal neurons, astrocytes and microglia. Membrane targets for extracellular cGMP are still poorly understood and must be addressed in future studies.

Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer's Disease.

Stem cell therapy improves memory loss and cognitive deficits in animal models with Alzheimer’s disease. The underlying mechanism remains to be determined, but it may involve the interaction of stem cells with hippocampal cells. The transplantation of stem cells alters the pathological state and establishes a novel balance based on multiple signaling pathways. The new balance mechanism is regulated by various autocrine and paracrine cytokines, including signal molecules that target (a) cell growth and death. Stem cell treatment stimulates neurogenesis and inhibits apoptosis, which is regulated by the crosstalk between apoptosis and autophagy—(b) Aβ and tau pathology. Aberrant Aβ plaques and neurofibrillary tau tangles are mitigated subsequent to stem cell intervention—(c) inflammation. Neuroinflammation in the lesion is relieved, which may be related to the microglial M1/M2 polarization—(d) immunoregulation. The transplanted stem cells modulate immune cells and shape the pathophysiological roles of immune-related genes such as TREM2, CR1, and CD33—(e) synaptogenesis. The functional reconstruction of synaptic connections can be promoted by stem cell therapy through multi-level signaling, such as autophagy, microglial activity, and remyelination. The regulation of new balance mechanism provides perspective and challenge for the treatment of Alzheimer’s disease.

Serotonergic-Muscarinic Interaction within the Prefrontal Cortex as a Novel Target to Reverse Schizophrenia-Related Cognitive Symptoms.

Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.

Crocus Sativus L. (Saffron) in Alzheimer's Disease Treatment: Bioactive Effects on Cognitive Impairment.

Crocus sativus L. (saffron) appears to own neuroprotective effects on cognitive impairment in patients with Alzheimer's disease (AD). The purpose of this work is to review evidence and mechanisms of saffron-induced therapeutic outcomes and measureable cognitive benefits in AD. The literature was reviewed, and preclinical and clinical studies were identified. In vitro and in vivo preclinical studies were selected according to these criteria: 1) development of saffron pharmacological profile on biological or biophysical endpoints; 2) evaluation of saffron efficacy using animal screens as an AD model, and 3) duration of the studies of at least 3 months. As for the clinical studies, the selection criteria included: 1) patients aged ≥ 60, 2) AD diagnosis according to National Institute on Aging-Alzheimer's Association (NIAAA) criteria, and 3) appropriate procedures to assess cognitive, functional, and clinical status. A total of 1477 studies published until November 2020 were identified during an initial phase, of which 24 met the inclusion criteria and were selected for this review. Seventeen in vitro and in vivo preclinical studies have described the efficacy of saffron on cognitive impairment in animal models of AD, highlighting that crocin appears to be able to regulate glutamate levels, reduce oxidative stress, and modulate Aβ and tau protein aggregation. Only four clinical studies have indicated that the effects of saffron on cognitive impairment were not different from those produced by donepezil and memantine and that it had a better safety profile. Saffron and its compounds should be further investigated in order to consider them a safer alternative in AD treatment.

Nitric oxide role in anxiety-like behavior, memory and cognitive impairments in animal model of chronic migraine

The occurrence of cognitive dysfunctions and anxiety and mood disorders has been shown to be higher in migraine patients. Nitric Oxide (NO) is a significant neurotransmitter in the pathophysiology of migraine, anxiety and neurodegenerative disorders. Therefore, the present study was conducted to evaluate the role of NO system in migraine-induced memory impairment and anxiety like behaviors. Nitroglycerin (NTG) was administered to the animals as an animal model of migraine and pretreatment with L-Arginine, L-NAME and saline were implemented to evaluate the role of NO system in possible cognitive impairments in animal model of migraine. Avoidance learning and memory performance, object recognition memory, anxiety-like behavior and motor activity were assessed using a shuttle box apparatus, novel object recognition, elevated plus-maze, and open field tests respectively. The data showed that the injection of nitroglycerin disturbs learning and memory and elicit anxiety like behavior in the animals. L-NAME administration suppressed the observed effect of nitroglycerin on memory and anxiety. Overall, the results indicated that nitric oxide system is implicated in memory impairments and anxiety like behavior in an animal model of migraine.