Acetylcholine Levels Research Articles

The memory-improving effect of Hizikia forsiforme functional oil microcapsule (HFFOM) prepared by subcritical extraction and complex coacervational embedding

Functional foods are prospective in improving memory decline caused by Alzheimer’s disease and aging. The Edible seaweed Hizikia fusiforme functional oil (HFFO) inhibited acetylcholinesterase, prevented cellular neuroinflammation, and improved memory deficits in zebrafish models in the previous studies. To realize its greener preparation and lipid oxidation mitigation and study its effects on higher animals, more investigations are necessary. Herein, sub-critical fluid extraction of HFFO and successive complex coacervation embedding yielded a water-soluble and anti-oxidative microcapsule HFFOM, which displayed in vivo memory-improving effects on LPS-injured zebrafish and normal rodents in different behavior tests. HFFOM can elevate the level of the neurotransmitter acetylcholine while decreasing the levels of MDA, IL-1β, and TNF-α in the zebrafish brain. LC-MS/MS and lipidomic analysis suggested its predominant memory-improving ingredients to be linolenic, erucic, nervonic, arachidonic, linoleic, eicosatrienoic, docosahexaenoic, and docosapentaenoic acids. This study enlightens the potential of HFFOM in developing memory-enhancing functional foods or drugs.

Review on Alzheimers Disease

Abstract: Loss of Abstract Thinking Someone with Alzheimer’s disease may lose the ability to draw conclusions and solve problems. It may become difficult to balance a checkbook, for example, because the patient has forgotten what to do with the numbers. About 29.8 million people worldwide had been diagnosed with Alzheimer’s disease (AD) in 2015, And the number is projected to triple by 2050. In 2018, AD was the fifth leading cause of death in Americans with 65 years of age or older, but the progress of AD drug research is very limited. It is Helpful to identify the key factors and research trends of AD for guiding further more effective Studies. Alzheimer’s disease is a degenerative disease of the brain, the most common cause of dementia in the geriatric population, and a major cause of death. Alzheimer’s disease is one of the fastest growing risk factors in middle age, which Increases the risk of Alzheimer’s disease in coronary weddings and higher levels of Homocysteine, which can lead to withdrawal due to lifestyle changes. Cigarettes prevent Alzheimer’s disease by recalling memories. Also, despite the fact that there is no Definitive cure for Alzheimer’s, the ability to increase acetylcholine levels and reduce Ameloid beta deposition and your medications such as Donepezil has proven to be very Effective when treating Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It Is characterized by progressive cognitive deterioration together with Declining activities of daily living and behavioral changes. It is the Most common type of pre-senile and senile dementia. Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence Extracellular b-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphos . Phorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles For other critical cellular and molecular processes. Despite this, no disease-modifying treatment Currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here ,We review recent advances in our understanding of AD pathobiology and discuss current treatment Strategies, highlighting recent clinical trials and opportunities for developing future disease modifying therapies.

Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor

Background/Aims: Lead exposure is known to induce oxidative stress and neurotoxicity. Nitric oxide (NO) plays an important role in modulating oxidative stress, with L-arginine as a precursor of NO and Nω-nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine. Methods: This study investigated the differential effects of L-arginine and L-NNA on markers of oxidative stress and biochemical changes in brain tissue from rats with different levels of resistance to hypoxia exposed to lead nitrate. Rats with either low or high resistance to hypoxia were exposed to lead nitrate (oral 3.6 mg lead nitrate/kg b.w. per day for 30 days) and treated with L-arginine (600 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate) or L-NNA (35 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate). Brain tissue samples were analysed for lipid peroxidation, oxidative modification of proteins, and activity of antioxidant enzymes, including superoxide dismutase, catalase, glutathione reductase, and peroxidase, and total antioxidant status (TAS). We also examined the biomarkers of biochemical pathways involving the activity of alanine and aspartate aminotransferases, succinate dehydrogenase (SDH), and α-ketoglutarate dehydrogenase (KGDH). In addition, the trend observed was supported by assessments of the acetylcholine levels and acetylcholinesterase activity (ACh-AChE system) in brain tissue. Results: In rats with low resistance to hypoxia, the L-arginine treatment significantly reduced lipid peroxidation and oxidative protein modification but increased antioxidant enzyme activity, suggesting a protective effect against lead-induced oxidative stress. Conversely, in rats with high resistance to hypoxia, L-NNA had a protective effect, reducing lead-induced oxidative damage and decreasing lipid peroxidation, whereas L-arginine exacerbated oxidative stress and impaired antioxidant defences. These findings were supported by corresponding changes in the acetylcholine-acetylcholinesterase system, reflecting the observed patterns of lead-induced oxidative stress and neurotoxicity. The study shows that L-arginine exerts a protective effect by reducing lead-induced oxidative damage via an improvement in TAS. Our study shows that lead nitrate exposure significantly increases ala-nine and aspartate aminotransferase activity in brain tissue, with L-arginine exacerbating and L-NNA reversing this effect. The lead nitrate exposure also affected the activities of SDH and KGDH, which are important for cellular energy production and hypoxia resistance, with L-arginine altering SDH activity depending on the level of resistance and L-NNA enhancing both SDH and KGDH activities. These trends were further validated by alterations in the ACh-AChE system, highlighting the differential role of NO-dependent mechanisms in modulating lead-induced neurotoxicity based on hypoxia resistance. Conclusion: These findings suggest potential targeted therapeutic strategies based on the oxidative stress profile and highlight the potential of nitric oxide system modulators in counteracting lead-induced biochemical alterations and the dynamics of the ACh-AChE system depending on the individual physiological reactivity of organisms.

Anticholinesterase, Antioxidative and Neuroprotective Effects of Hydroethanolic Extracts of Guiera Senegalensis J. F. Gmel. Leaves on Scopolamine Induced Alzheimer’s Disease in Wistar Rat Models

Background: Medicinal plants like Guiera senegalensis J. F. Gmel. (GS) have gained attention for their potential neuroprotective effects due to their rich composition of bioactive compounds, including flavonoids and polyphenolic acids. While previous studies have highlighted the antioxidant, anti-inflammatory, and neuroplasticity-enhancing properties of GS extract, its efficacy in mitigating dementia-related pathology remains to be fully understood. Objectives: This study aimed to investigate the neuroprotective effects of hydroethanolic GS extract against scopolamine (Sco)-induced dementia in Wistar rats, focusing on its impact on cholinergic function, oxidative stress, neuroinflammation, neurodegeneration, and memory impairment. Methods: Fresh leaves were processed for extraction using standard methods. Antioxidant activity was evaluated using FRAP and DPPH assays. Adult male Wistar rats were used for behavioral tests (Y-maze, NOR, MWM) and biochemical analyses, including ELISA for cholinergic activity, oxidative stress markers (Aβ1-42, phosphorylated Tau), pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IFN-γ), GFAP, BDNF, and IL-10. Brain tissues underwent histopathological examination. Data were analyzed using GraphPad Prism software. Results: The study assessed the antioxidant potential of GS extract and found that it significantly scavenged DPPH radicals (70.29%) and reduced Fe3+ (49.69%). Behavioral tests showed that GS extract (100 - 400 mg/kg) improved spatial memory and learning in Sco-treated rats. Y-maze results indicated increased spontaneous alternation with GS extract (P < 0.01). NOR and MWM tests showed improved memory and learning, with GS extract-treated rats spending more time in the target quadrant. Biochemical analysis revealed that GS extract increased acetylcholine (ACh), Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH), IL-10, and BDNF levels, while decreasing acetylcholinesterase (AChE), malondialdehyde (MDA), nitrite, Aβ1-42, phosphorylated Tau, IL-1β, TNF-α, IL-6, IFN-γ, and GFAP levels in the hippocampus. Histological analysis confirmed restored hippocampal tissue architecture in AD rats treated with GS extract. Conclusions: Our findings suggest that GS modulates cholinergic, antioxidant, anti-inflammatory, and neuroplasticity pathways, exerting beneficial effects on cognitive functions and biochemical markers associated with Alzheimer's disease (AD) pathology. These results indicate the potential of GS as a neuroprotective agent for the treatment of AD.

Medial prefrontal cortex acetylcholine signaling mediates the ability to learn an active avoidance response following learned helplessness training.

Increased brain levels of acetylcholine (ACh) have been observed in patients with depression, and increasing ACh levels pharmacologically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that excessive ACh signaling results in strengthening of negative encoding in which memory formation is aberrantly strengthened for stressful events. The medial prefrontal cortex (mPFC) is critical for both top-down control of stress-related circuits, and for encoding of sensory experiences. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevation of ACh contributes to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to stress-based learning differentially in males and females.

Phytochemical Analysis, Antioxidant Activity and Bioassay-Guided Isolation of Acetylcholinesterase and Butyrylcholinesterase Inhibitors from Horsfieldia polyspherula Bark (Myristicaceae).

Alzheimer's disease (AD) is a neurodegenerative condition brought on by aging and characterised by progressive decline in cognitive function and abnormalities in the central cholnergic system. β-amyloid deposits, neurofibril tangle aggregation, oxidative stress or reduced level of acetylcholine are a few causes that have been linked to AD. In this study, the bioassay-guided isolation from ethyl acetate (EtOAc) extract of Horsfieldia polyspherula bark led to the isolation of nine compounds namely, 16-phenylhexadecanoic acid (1), undecylbenzene (2), 3,4-dihydroxybenzoic acid (3), dodecanoic acid (4), tetradecanoic acid (5), pentadecanoic acid (6), 1-tridecene (7), stigmasterol (8) and trimyristin (9). Phytochemical analysis revealed the presence of flavonoids, steroids, lignin, alkaloids, phytosterol and triterpenoids. The DPPH scavenging activity of EtOAc extract was related to the phenolic content (116.67 ± 16.98 GAE mg/g) and other non-phenolics such as lower fatty acids. Meanwhile, the DPPH scavenging activity was found to be concentration-dependent and correlated with both flavonoid and phenolic content. Furthermore, EtOAc and methanol (MeOH) extracts of H. polyspherula bark showed significant inhibitory activity at 100 μg/mL on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with EtOAc extract showing 77.2% and 64.1% inhibition and MeOH extract showing 37.5% and 39.2% inhibition, respectively. Additionally, the IC50 for BuChE and AChE of the EtOAc extract were found to be effective, with 15.41 ± 0.78 μg/mL and 7.67 ± 0.13 μg/mL, respectively. Compound 1 exhibited dual inhibition of 40.99 ± 1.99 μM (BuChE) and 46.83 ± 2.44 μM (AChE), while compounds 2 and 3 showed IC50 values above 200 μM. This study revealed that this plant shows a significant potential as anti-cholinesterase focusing on acetylcholinesterase (AchE) and butyrylcholinesterase (BuChE). This is the first report on Horsfieldia polyspherula and their biological activity.

Tropisetron, an Antiemetic Drug, Exerts an Anti-Epileptic Effect Through the Activation of α7nAChRs in a Rat Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti-epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined. In this study, tropisetron was intraperitoneally injected into pilocarpine-induced epileptic rats for 3 weeks. Alpha-bungarotoxin (α-bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ-aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse-associated protein (F-actin, cofilin-1) were quantified. The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m6A modification of cofilin-1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α-bgt. In summary, these findings indicate that tropisetron exhibits an anti-epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti-epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE.

Sida corymbosa prevents seizures and memory deficit via inhibition of oxidative stress and neuronal loss in the hippocampus

Mesiotemporal lobe epilepsy is the most refractory form of epilepsy. The management of this condition relies on the use of antiepileptic drugs known to provide symptomatic relief. Herbal remedies are therefore an alternative to finding a cure for epilepsy. The present study aimed to assess the antiepileptic and anti-amnesic effects of Sida corymbosa aqueous extract using the pentylenetetrazole (PTZ) kindling model in rats. For this, 48 rats were divided into 6 groups of 8 animals each and treated as follows: normal and negative controls received per os (p.o) distilled water (10 mL/kg); experimental groups received S. corymbosa extract (17.14, 34.28, and 68.56 mg/kg, p.o); and positive control group received levetiracetam (250 mg/kg, p.o). One hour after the treatments, animals intraperitoneally (i.p) received a subconvulsive dose of PTZ (25 mg/kg), except the normal control group. The animals were treated once daily until the onset of the first tonic-clonic seizure (stage 5) in the negative control group. Twenty-four hours following the onset of the first seizure, memory impairment was assessed. Twenty-four hours later, the animals were sacrificed, and the hippocampus and prefrontal cortex were collected for biochemical analyses. The extract (68.56 mg/kg) prevented (p < 0.001) seizures from day 1 to day 12 compared to the negative control group. The extract (17.14 and 34.28 mg/kg) increased the recognition index by 80 % (p < 0.05) and 60 % (p < 0.01), respectively, compared with the negative control group. Moreover, the extract (17.14 mg/kg) increased by 68 % (p < 0.001) the concentration of GABA in the hippocampus. The extract (17.14 and 34.28 mg/kg) increased the acetylcholine level by 51 % (p < 0.001) and 69 % (p < 0.001) in the hippocampus, respectively. The extract at a dose of 17.14 mg/kg decreased the concentration of MDA in the hippocampus by 43 % (p < 0.001). These findings suggest that the extract has antiepileptic and anti-amnesic potentials that could justify its empirical use.

Comparative assessment of acute neurotoxicity of real-world ultra-fine black carbon emitted from residential solid fuel combustion

Incomplete combustion of residential solid fuel is one of the main anthropogenic sources for black carbon (BC). Fresh BC, mainly enriched in ultra-fine fraction of particles, can directly cross blood-brain barrier and are reported to be associated with neurodegenerative diseases. Because of the difficulties in collection and purification of BC from ambient particles, there are still significant knowledge gaps in understanding neurotoxicity caused by real-world BC. The purpose of this study is to compare the neurotoxic effects caused by BCs emitted from combustion of six residential solid fuels, and try to reveal associated biological mechanisms in SH-SY5Y cells. Two straw BC (Wheat-BC and Corn-BC) showed highest neurotoxic effects followed by wood BC (Pine-BC and Aspen-BC) and coal BC (Xvzhou and Longkou Coal), as indicated by viability, lactic dehydrogenase, malondialdehyde, adenosine triphosphate and acetylcholine levels. Coal BC caused nearly no toxicity in human neuroblastoma (SH-SY5Y) cells within highest dose of 200 μg/mL. RNA sequence and bioinformatics analysis were applied to effectively identify differential genes and signaling pathways. Based on Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Protein Protein Interaction network (PPI network) construction, we found biomass BC affected mitochondrial function, interfered with cellular metabolic processes, disturbed redox homeostasis, and finally resulted in cellular damages. Coal-BC mainly caused cytokine/chemokine related inflammatory responses. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting methods were further applied to find out related signaling pathways. Biomass BC activated IL6R/JAK3/STAT3 and JAK3/STAT6 pathways leading to oxidative stress and inflammatory responses. Coal BC activated JAK3/STAT3 pathway leading to chemokine related responses. This study revealed the heterogeneity in neurotoxicity of BCs from different combustion sources and provided important data for health risk assessment. BC-related neurotoxicity should be considered when making air pollution emission control strategies, with residential biomass receiving more policy attention.

Acetylcholine and Depression: Scrutinizing Future Therapeutic Targets for Novel Drug Development

Depression, a pervasive and disabling mental health disorder, presents a global healthcare challenge. Despite persistent research on its etiology and pathophysiology, many aspects remain unclear. Predominant neurobiological research and traditional pharmacotherapies have pointed out the monoamine hypothesis as a pivotal factor in the pathophysiology of depression. However, emerging perspectives on the monoamine hypothesis highlight the significance of the cholinergic system, a major regulator of diverse CNS functions encompassing attention, arousal, cognition, and memory. Cognitive impairments were frequently observed in depression along with other symptoms i.e. low mood and anhedonia. A comprehensive literature search was conducted across multiple databases (PubMed, Scopus, and Web of Science) from their inception until May 2023. We screened 1,200 articles, of which 400 full-text articles were assessed for eligibility, and 231 studies met the inclusion criteria. The review included both pre-clinical and clinical studies focusing on the role of acetylcholine (ACh) and its receptors in depression. Data extraction and quality assessment were performed independently by two reviewers. In literature, both pre-clinical and clinical studies suggest that elevated central ACh levels may contribute to depression, prompting investigations into intervention strategies targeting mAChRs/nAChRs and AChE. These receptors have become a critical target in drug-design strategies aimed at addressing depression-like symptoms. In addition, research has demonstrated a significant antidepressant-like effect of AChEIs in a dose-dependent manner in animal models. Hence, this evidence over the past decades underscores the pivotal role of the cholinergic system in mood regulation, offering promise for novel depression treatments. In this review, we tried to summarize the historical evolution of the cholinergic system from early discoveries to its role in the pathophysiology of depression. It presents evidence for the involvement of mAChRs and nAChRs, as well as AChE, in depression. By outlining the cholinergic theory of depression, this review suggests a novel therapeutic approach, emphasizing the role of ACh in the complex depression pathophysiology, and presenting avenues for further research and the development of targeted interventions.

Neuroinflammation and oxidative redox imbalance drive memory dysfunction in adolescent rats prenatally exposed to Datura Stramonium

Although there have been reports indicating that Datura Stramonium (D. stramonium) may induce anticholinergic and neuropsychiatry effects, the compound is still being used for recreational and medicinal purposes while ingestion during pregnancy has been documented. Intriguingly, minimal studies have investigated the potential neurotoxic impact of D. stramonium exposure at various stages of gestation, including its potential implication on neurophysiological well-being later in life. The present study, therefore, examined spontaneous working memory and the expression of specific neurochemicals modulating crucial neural processes in adolescent rats exposed to high and low D. stramonium doses during different stages of gestation. Pregnant rats were orally infused with 150- or 500- mg/kg/day of D. stramonium either during mid- (second week; days 8–14) or late- (third week; days 15–21) gestation, while control rats received PBS at dosing periods. Behavioral characterization of offspring between postnatal days (PD) 40 and 41 in the Y-maze revealed that D. stramonium perturbed spatial working memory in rats, although locomotor activity was generally unaltered. In addition to SOD and nitric oxide downregulation, induction of oxidative stress in the hippocampus and prefrontal cortex (PFC) of young adult rats prenatally exposed to D. stramonium was corroborated by depletion of key antioxidant regulatory elements glutathione peroxidase, glutathione reductase and catalase, which was accompanied by lipid peroxidation shown by increased MDA levels. Whereas increased expression of acetylcholinesterase and LDH was seen in adolescent rats prenatally infused D. stramonium, acetylcholine levels were downregulated in both hippocampal and PFC lysates, suggesting cholinergic and metabolic dysfunctions. Immunohistochemical labelling of GFAP and IBA-1 revealed increased expression of reactive astrocytes and microglia respectively, while the accompanying TNFα upregulation in both the hippocampus (dentate gyrus) and PFC causally linked intrauterine D. stramonium exposure with neuroinflammatory responses postnatally. Overall, our data correlated postnatal spatial working memory dysfunction evoked by D. stramonium exposure during critical stages of embryonic development to oxidative redox impairment, cholinergic disruption and neuroinflammatory perturbations in rats.

Neuroprotective Effects of Bryophyllum pinnatum against Ketamine-Induced Neurotoxicity in Wistar Rats: Neurochemical, Oxidative Stress, and Histological Investigation

Background: This study evaluated the neuroprotective effects of Bryophyllum pinnatum (B. pinnatum) in ketamine-induced neurotoxicity in Wistar rats, focusing on neurochemical and oxidative stress markers, as well as histological changes in the hippocampus and cerebral cortex. Methods: Sixty male Wistar rats were divided into six groups. Group 1 received normal saline (2ml), Group 2 was administered ketamine (20mg/kg), and Group 3 received risperidone (0.5mg/kg). Groups 4, 5, and 6 were treated with B. pinnatum at 50mg/kg, 100mg/kg, and 200mg/kg, respectively for a duration of 21 days after induction of toxicity. Neurochemical markers (dopamine, glutamate, GABA, serotonin, noradrenaline, acetylcholine), oxidative stress markers (GSH, MDA, SOD, CAT, GPx), and histological analysis of brain tissues were evaluated after treatment periods of one, two, and three weeks. Results: Ketamine administration significantly reduced dopamine, GABA, serotonin, and noradrenaline levels while increasing acetylcholine and glutamate levels (p&lt;0.05). B. pinnatum treatment reversed these effects in a dose-dependent manner, particularly at high doses. Oxidative markers showed reduced GSH and increased MDA levels with ketamine, which B. pinnatum mitigated significantly (p&lt;0.05). Histologically, ketamine caused neuronal degeneration and microstructural distortion in the hippocampus and cerebral cortex, which were markedly reduced by B. pinnatum, especially at 200mg/kg, showing well-preserved neuronal structures. Conclusion: B. pinnatum demonstrates significant neuroprotective effects against ketamine-induced neurotoxicity by modulating neurochemical and oxidative markers and preserving histological integrity in brain tissues, suggesting its potential therapeutic application in neurotoxic conditions.

Novel Therapeutic Approaches in Alzheimer's Disease

Alzheimer's disease (AD) is a neurological condition associated with a decrease in levels of acetylcholine and diminished cholinergic functions. This may be caused by the degeneration of cholinergic neurons in the brain, leading to cognitive deficits. Due to the difficulty and invasiveness of collecting cerebrospinal fluid (CSF) required for assessing conventional biomarkers, researchers are currently exploring less intrusive, less expensive, and more straightforward methods for diagnosing AD. Additionally, conventional interventions such as cholinesterase inhibitors like rivastigmine, donepezil, and galantamine are US FDA-approved drugs that are still effective for managing AD. The goal of this therapy is to increase acetylcholine levels in the brain by inhibiting the enzymes that degrade acetylcholine. Therefore, this therapeutic approach is useful for treating mild-to-moderate AD. However, only symptomatic treatment is currently available, and it can lead to serious adverse effects from conventional therapy. Thus, novel therapies for AD are needed in a growing global population. This manuscript provides information on various biomarkers with possible pathogenesis mechanisms, novel treatment strategies such as microalgae, HupA, cannabinoids, and the beneficial effects of coenzyme Q10, bacterial probiotics, omega-3 fatty acids, vitamin B12, and D3 in memory impairment for managing AD. Non-pharmacological treatments such as music therapy, Electroacupuncture (EA), or manual acupuncture (MA) also play an important role in enhancing the effectiveness of conventional pharmacological treatments for AD.

Microwave-Assisted Synthesis of Indoloquinoxaline Derivatives as Promising Anti-Alzheimer agents: DFT and Molecular docking Study

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. One of the major pathological features of AD is the degeneration of cholinergic neurons and associated loss of acetylcholine (ACh), a key neurotransmitter involved in memory and cognition. Reduced ACh levels correlate with the severity of cognitive symptoms in AD. Thus, inhibition of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh, is a leading treatment strategy. This study aimed to synthesize and evaluate novel AChE inhibitors based on an indolo[2,3-b]quinoxaline scaffold. A series of indolo[2,3-b]quinoxaline derivatives were designed by molecular hybridization of indole and quinoxaline privileged structures. Microwave-assisted synthesis improved the efficiency of obtaining the desired compounds. In vitro screening identified several potent AChE inhibitors, with IC50 values down to 0.02 µM. The most active compounds contained electron-withdrawing groups like nitro and benzoyl moieties. DFT calculations provided insights into geometrical, thermal, and electronic properties of the compounds. FMO analysis revealed variations in HOMO and LUMO energies that impact reactivity. Molecular docking elucidated binding modes, highlighting the pi-pi, pi-H, and H-bonding interactions with key amino acids in the catalytic gorge of AChE. Overall, the indole-quinoxaline hybrids represent promising candidates for development of novel dual binding site AChE inhibitors and multifunctional anti-Alzheimer agents.

Properties of layer V pyramidal neurons in the primary motor cortex that represent acquired motor skills

Layer V neurons in primary motor cortex (M1) are required for motor skill learning. We analyzed training-induced plasticity using a whole-cell slice patch-clamp technique with a rotor rod task, and found that training induces diverse changes in intrinsic properties and synaptic plasticity in M1 layer V neurons. Although the causal relationship between specific cellular changes and motor performance is unclear, by linking individual motor performance to cellular/synaptic functions, we identified several cellular and synaptic parameters that represent acquired motor skills. With respect to cellular properties, motor performance was positively correlated with resting membrane potential and fast afterhyperpolarization, but not with the membrane resistance, capacitance, or threshold. With respect to synaptic function, the performance was positively correlated with AMPA receptor-mediated postsynaptic currents, but not with GABAA receptor-mediated postsynaptic currents. With respect to live imaging analysis in Thy1-YFP mice, we further demonstrated a cross-correlation between motor performance, spine head volume, and self-entropy per spine. In the present study, we identified several changes in M1 layer V pyramidal neurons after motor training that represent acquired motor skills. Furthermore, training increased extracellular acetylcholine levels known to promote synaptic plasticity, which is correlated with individual motor performance. These results suggest that systematic control of specific intracellular parameters and enhancement of synaptic plasticity in M1 layer V neurons may be useful for improving motor skills.

Betahistine's Neuroprotective Actions against Lipopolysaccharide-Induced Neurotoxicity: Insights from Experimental and Computational Studies.

Histamine H3 receptor (H3R) antagonists, such as betahistine (BHTE), have shown significant potential in treating central nervous system (CNS) disorders due to their neuroprotective properties. This study investigated BHTE's effects on lipopolysaccharide (LPS)-induced neurotoxicity, which is associated with neuroinflammation and neurodegeneration. Rats were divided into groups and pre-treated with BHTE (5 or 10 mg/kg, p.o.) for 30 days, followed by LPS administration (1 mg/kg, i.p.) for 4 consecutive days to induce neurotoxicity. LPS exposure resulted in cognitive impairment, as evidenced by performance deficits in maze tests, and a significant reduction in brain acetylcholine (ACh) levels. Additionally, LPS led to increased neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Pre-treatment with BHTE effectively counteracted these effects, improving cognitive performance and restoring ACh levels. BHTE significantly reduced LPS-induced increases in pro-inflammatory markers (COX-2, TNF-α, and IL-6) while enhancing anti-inflammatory cytokines (IL-10 and TGF-β1). Furthermore, BHTE improved mitochondrial function by increasing enzyme levels (MRCC-I, II, and IV) and boosted anti-apoptotic (Bcl-2) and antioxidant defenses (GSH and catalase). BHTE also reduced apoptosis markers, including pro-apoptotic protein caspase-3, and oxidative stress marker malondialdehyde (MDA). Molecular modeling studies revealed that BHTE effectively binds to key enzymes involved in neuroinflammation and apoptosis (AChE, COX-2, and caspase-3), with binding free energies between 4 and 5 kcal/mol, interacting with critical residues. These findings underscore BHTE's multifaceted neuroprotective effects against LPS-induced neurotoxicity, offering potential therapeutic avenues for managing neuroinflammation and related neurodegenerative disorders.

Cannabidiol enhances socially transmitted food preference: a role of acetylcholine in the mouse basal forebrain.

Rodents acquire food information from their conspecifics and display a preference for the conspecifics' consumed food. This social learning of food information from others promotes the survival of a species, and it is introduced as the socially transmitted food preference (STFP) task. The cholinergic system in the basal forebrain plays a role in the acquisition of STFP. Cannabidiol (CBD), one of the most abundant phytocannabinoids, exerts its therapeutic potential for cognitive deficits through versatile mechanisms of action, including its interaction with the cholinergic system. We hypothesize a positive relationship between CBD and STFP because acetylcholine (ACh) is involved in STFP, and CBD increases the ACh levels in the basal forebrain. Male C57BL/6J mice were trained to acquire the STFP task. We examined whether CBD affects STFP memory by administering CBD (20mg/kg, i.p.) before the STFP social training. The involvement of cholinergic system in CBD's effect on STFP was examined by knockdown of brain acetylcholinesterase (AChE), applying a nonselective muscarinic antagonist SCO (3mg/kg, i.p.) before CBD treatment, and measuring the basal forebrain ACh levels in the CBD-treated mice. We first showed that CBD enhanced STFP memory. Knockdown of brain AChE also enhanced STFP memory, which mimicked CBD's effect on STFP. SCO blocked CBD's memory-enhancing effect on STFP. Our most significant finding is that the basal forebrain ACh levels in the CBD-treated mice, but not their control counterparts, were positively correlated with mice's STFP memory performance. This study indicates that CBD enhances STFP memory in mice. Specifically, those which respond to CBD by increasing the muscarinic-mediated ACh signaling perform better in their STFP memory.

Toxic Features and Metabolomic Intervention of Glabrene, an Impurity Found in the Pharmaceutical Product of Glabridin.

Glabridin is a widely used product in the cosmetics and pharmaceutical industry, which is generally isolated and purified from Licorice (Glycyrrhiza glabra) extract in industrial production. It has wide clinical applications, but significant toxicity has also been reported. The purity of glabridin raw material is generally between 90% and 98%. We have identified a toxic impurity, glabrene, in the industrial product glabridin. Our investigation using an AB wild-type zebrafish toxicity test showed that glabrene has a significant lethal effect with an LC10 of 2.8 μM. Glabrene induced obvious malformation and disrupted cartilage development in zebrafish larvae. Furthermore, the compound significantly reduced larval mobility and caused damage to brain neural tissues. Metabolic pathway analysis and neurotransmitter quantification via ELISA indicated abnormal activation of the phenylalanine metabolic pathway, resulting in elevated dopamine and acetylcholine levels in vivo. These findings provide insights into the potential risks of glabrene contamination and offer a new reference point for enhancing safety measures and quality controls in licorice-derived products.

Morin attenuated the global cerebral ischemia via antioxidant, anti-inflammatory, and antiapoptotic mechanisms in rats.

Global cerebral ischemia is one of the major causes of memory and cognitive impairment. Hyperactivation of acetylcholine esterase (AChE), oxidative stress, and inflammation are reported to cause memory and cognitive impairment in global cerebral ischemia. Morin, a flavonoid, is reported to have neuroprotective properties through its antioxidant and anti-inflammatory in multiple neurological diseases. However, its neuroprotective effects and memory and cognition enhancement have not yet been investigated. In the present study, we have determined the memory and cognition, and neuroprotective activity of Morin in bilateral common carotid artery occlusion and reperfusion (BCCAO/R) in Wistar rats. We found that Morin treatment significantly improved motor performance like grip strength and rotarod. Further, Morin improved memory and cognition in BCCAO rats by decreasing the AchE enzyme activity and enhancing the acetylcholine (Ach) levels. Additionally, Morin exhibited neuroprotection by ameliorating oxidative stress, neuroinflammation, and apoptosis in BCCAO rats. These findings confirm that Morin could enhance memory and cognition by ameliorating AchE activity, oxidative stress, neuroinflammation, and apoptosis in global cerebral ischemia. Therefore, Morin could be a promising neuroprotective and memory enhancer against global cerebral ischemic injury.

Neurotransmitter acetylcholine mediates the mummification of Ophiocordyceps sinensis-infected Thitarodes xiaojinensis larvae.

Parasites can manipulate host behavior to facilitate parasite transmission. One such host-pathogen interaction occurs between the fungus Ophiocordyceps sinensis and the ghost moth Thitarodes xiaojinensis. O. sinensis is involved in the mummification process of infected host larvae. However, the underlying molecular and chemical mechanism for this phenomenon is unknown. We characterized the small molecules regulating host behaviors and the altered metabolites in infected and mummified host larvae. Lipid-related metabolites, such as phosphatidylcholine, were identified in infected and mummified larvae. Decreased levels of the neurotransmitter acetylcholine (ACh) and elevated choline levels were observed in the brains of both the infected and mummified larvae. The aberrant activity of acetylcholinesterase (AChE) and relative mRNA expression of ACE2 (acetylcholinesterase) may mediate the altered transformation between ACh and choline, leading to the brain dysfunction of mummified larvae. Caspofungin treatment inhibited the mummification of infected larvae and the activity of AChE. These findings indicate the importance of ACh in the mummification of host larvae after O. sinensis infection.IMPORTANCEOphiocordyceps sinensis-infected ghost moth larvae are manipulated to move to the soil surface with their heads up in death. A fruiting body then grows from the caterpillar's head, eventually producing conidia for dispersal. However, the underlying molecular and chemical mechanism has not been characterized. In this study, we describe the metabolic profile of Thitarodes xiaojinensis host larvae after O. sinensis infection. Altered metabolites, particularly lipid-related metabolites, were identified in infected and mummified larvae, suggesting that lipids are important in O. sinensis-mediated behavioral manipulation of host larvae. Decreased levels of the neurotransmitter acetylcholine were observed in both infected and mummified larvae brains. This suggests that altered or reduced acetylcholine can mediate brain dysfunction and lead to aberrant behavior. These results reveal the critical role of acetylcholine in the mummification process of infected host larvae.