Search Results (82)

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and there are still no strategies to slow or prevent its clinical progression. Significant financial and research resources have been invested into studying the pathology of AD. However, its pathogenesis is not fully understood. This review provides a comprehensive analysis of current understanding of AD pathogenesis, including classical hypotheses (amyloid cascade, tau pathology, neuroinflammation, oxidative stress), emerging mechanisms (cellular senescence, endoplasmic reticulum stress, ubiquitin-proteasome system dysfunction), and alternative mechanisms (cholinergic dysfunction, glutamate excitotoxicity, disruption of the microbiota–gut–brain axis, and autophagy). Schematic illustrations summarize the relationships between the hypotheses and their role in the pathogenesis of AD. Particular attention is paid to the systematization of promising biological targets and the analysis of modern ligands of various nature, including small molecules, peptides, antibodies and their fragments, natural compounds, as well as innovative hybrid and multifunctional structures. A separate section is devoted to radiopharmaceuticals for PET imaging (Florbetaben, Flortaucipir, etc.) and promising therapeutic agents. Thus, in this review we (1) systematize modern concepts of AD pathogenesis, including classical, emerging mechanisms and alternative hypotheses; (2) conduct a comparative analysis of ligand classes (small molecules, peptides, antibodies, etc.) and their therapeutic potential; and (3) discuss the clinical prospects of radiopharmaceuticals for PET imaging and targeted therapy. The work provides a comprehensive analysis of modern approaches, which can help in the development of more effective drugs against AD. Full article

Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in vitro and in vivo systems. These observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set up a cellular model composed of human induced pluripotent stem cell (hiPSC)-derived neurons (dopaminergic for PD and cholinergic for AD) exposed to inflamed glial medium [α-synuclein pre-formed fibrils (α-syn pffs) for PD and amyloid-β (Aβ)_1–42 fibrils for AD] for several days. To dissect the effect of neuroinflammation, and specifically, the role of LRRK2, on neuronal functions, we first performed transcriptome analysis, and then, we validated the results at functional levels. Interestingly, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both ND contexts and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through LRRK2 pharmacological inhibition might limit the progression of NDs and thus be neuroprotective. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management. Full article

Alzheimer’s disease (AD) is characterized by the progressive loss of cognitive function and is frequently accompanied by neuropsychiatric symptoms (NPS). Pathologically, AD is defined by two hallmark features: the extracellular accumulation of β-amyloid and the intracellular hyperphosphorylation of the tau protein. In addition to these primary changes, several other abnormalities are associated with the disease, including neuroinflammation, synaptic loss, oxidative stress, neurotransmitter imbalance, and genetic and epigenetic alterations. NPS in AD encompass a range of symptoms, such as anxiety, apathy, agitation, depression, and psychosis. These symptoms are thought to arise partly from the damage caused by the pathological hallmarks of AD, which impair various neurotransmitter systems. Altered levels of several neurotransmitters, including gamma-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA), and the cholinergic and noradrenergic systems, have been implicated in the development of agitation. Additionally, reduced endocannabinoid system (ECS) functionality, particularly cannabinoid receptor 1 (CB1R), has been linked to neurobehavioral alterations. Preclinical studies suggest that a decrease in CB1R levels is associated with aggressive behavior, and CB1R agonists have demonstrated beneficial effects in alleviating agitation and related symptoms. Given these findings, the current review focuses on the therapeutic potential of targeting neurotransmitter systems and CB1R dysfunction to manage agitation in AD. Full article

Background: Alzheimer’s disease (AD) is the most common cause of dementia. In addition to cognitive decline, non-cognitive symptoms, including dysautonomia, have been reported, although these symptoms are rarely acknowledged by patients. Dysautonomia in AD is thought to arise from either cholinergic deficits or hypothalamic involvement. A wide range of tests has been used to investigate the role of the autonomic nervous system; however, the results have been inconsistent. Aim: To systematically review all published research investigating autonomic nervous system (ANS) involvement in patients with AD. A comprehensive literature search was conducted in December 2024 across the following databases: PubMed, Cochrane Library, ScienceDirect, and Scopus. Results: A total of 1422 records were identified, of which 30 studies fulfilled the inclusion criteria and were included in the review. Several autonomic tests were employed, with Heart Rate Variability (HRV) being the most frequently used. Other tests included assessments of orthostatic hypotension (OH), postprandial hypotension (PPH), sympathetic skin response (SSR), the tilt test, 123I-MIBG cardiac scintigraphy, norepinephrine (NE) measurements in serum and cerebrospinal fluid, and baroreflex sensitivity. In most studies, AD patients were compared to either healthy controls or patients with other types of dementia. Discussion: The primary finding of this review is that, although patients with AD rarely report dysautonomic symptoms, they frequently exhibit abnormal results on various autonomic tests. In some cases, these findings were sufficient to differentiate AD patients from healthy controls as well as from patients with Diffuse Lewy Body disease (DLB). The inconsistency in reporting symptoms, along with the variability in test results, suggests that autonomic dysfunction in AD may be under-recognized and warrants further investigation. Conclusions: The heterogeneity of the included studies limits the generalizability of the results. However, given the potential impact of dysautonomia on both quality of life and mortality, it is recommended that AD patients be systematically assessed for autonomic dysfunction. Even in the absence of overt symptoms, appropriate treatment should be considered where indicated to mitigate potential risks. Full article

Background and Objectives: Subthreshold depression (StD) presents with depressive symptoms similar to major depressive disorder (MDD) but of lower intensity. Despite its milder form, StD is significantly prevalent in the older population, affecting up to 12.9%. StD is associated with adverse outcomes, such as an increased risk of MDD and mild cognitive impairment (MCI). Treating StD in older adults is challenging due to the limited efficacy and side effects of traditional antidepressants. As a result, clinicians often adopt a “watchful waiting” strategy, which increases the risk of StD progressing into MDD or MCI. Choline alphoscerate (α-GPC), a cholinergic drug, is indicated in the treatment of pseudodepression in the elderly, a condition that corresponds to the actual definition of StD. This review highlights the role of α-GPC in the treatment of StD in older subjects. Methods: A comprehensive review of preclinical and clinical studies was conducted, focusing on the efficacy of α-GPC in improving cognitive and behavioral functions in mental conditions and in modulating neurotransmitter systems involved in depression, such as dopamine and serotonin. Results: Evidence points to the therapeutic benefits of using α-GPC in StD as it acts on cholinergic dysfunction and cognitive impairment. Additionally, it may improve mood regulation and motivation, key factors in StD and in depressive disorders. These findings suggest that α-GPC may reduce the risk of progression from StD to MDD or MCI. Conclusions: α-GPC represents an effective and safe therapeutic option for the treatment of StD in the older population, improving clinical outcomes and enhancing the quality of life in this high-risk group. Full article

Given its antioxidant effects and central nervous system benefits, we hypothesized that RJ6601 should improve neurodegeneration in the hippocampus, a region critical for cognition and the maintenance of quality of life (QoL). To assure its safety, a single fixed dose of 2000 mg/kg BW was administered to female Wistar rats (250–450 g, 18 months old) to test the acute toxicity of RJ6601. No mortality and toxicity signs were observed. To prove that RJ6601 can protect against age-related neurodegeneration, RJ6601 at doses of 200 and 400 mg/kg BW was administered to the female Wistar rats once daily for 4 weeks. At the end of the study period, assessments were conducted to evaluate the neuron density; MDA levels; and activities of SOD, CAT, GSH-Px, AChE, total MAO, MAO-A, and MAO-B in the hippocampus. Our results reveal increased neuron density, SOD, CAT, and GSH-Px but decreased MDA, AChE, total MAO, MAO-A, and MAO-B in the hippocampi of female Wistar rats subjected to RJ6601 treatment at both doses used in this study. Therefore, RJ6601 is considered to have low toxicity and may improve neurodegeneration as well as cholinergic and monoaminergic dysfunctions. Subchronic toxicity studies and clinical trials are essential to confirm the safety of RJ6601 consumption and its health benefits. Full article

Sleep bruxism (SB) involves involuntary jaw movements during sleep and is potentially caused by motor neuronal hyperexcitability and GABAergic system dysfunction. However, the molecular basis remains unclear. In this study, we aimed to investigate changes in the expression of several genes associated with the pathophysiology of SB. Bulk RNA sequencing (bulk RNA-seq) and single-nucleus RNA sequencing (snRNA-seq) of neurons derived from patient and control human induced pluripotent stem cells (hiPSCs) were performed to comprehensively assess gene expression and cell type-specific alterations, respectively. Bulk RNA-seq revealed significant upregulation of calcium signaling-related genes in SB neurons, including those encoding G protein-coupled receptors and receptor-operated calcium channels. snRNA-seq confirmed the increased expression of GRIN2B (an N-methyl-D-aspartate receptor subunit) and CHRM3 (an M3 muscarinic acetylcholine receptor), particularly in glutamatergic and GABAergic neurons. These alterations were linked to hyperexcitability, with GRIN2B contributing to glutamatergic signaling and CHRM3 contributing to cholinergic signaling. These findings suggest that disrupted calcium signaling and overexpression of GRIN2B and CHRM3 drive neuronal hyperexcitability, providing insight into the pathophysiology of SB. Targeting these pathways may inform therapeutic strategies for SB treatment. Full article

Cognitive impairment (CI) is a type of mental health disorder that mainly affects cognitive abilities, such as learning, memory, perception, and problem-solving. Currently, in clinical practice, the treatment of cognitive impairment mainly focuses on the application of cholinesterase inhibitors and NMDA receptor antagonists; however, there is no specific and effective drug yet. Procatechuic acid (PCA) possesses various functions, including antibacterial, antiasthmatic, and expectorant effects. In recent years, it has received growing attention in the cognitive domain. Therefore, by summarizing the mechanisms of action of procatechuic acid in the treatment of cognitive impairment in this paper, it is found that procatechuic acid has multiple effects, such as regulating the expression of neuroprotective factors, inhibiting cell apoptosis, promoting the autophagy-lysosome pathway, suppressing oxidative stress damage, inhibiting inflammatory responses, improving synaptic plasticity dysfunction, inhibiting Aβ deposition, reducing APP hydrolysis, enhancing the cholinergic system, and inhibiting the excitotoxicity of neuronal cells. The involved signaling pathways include activating Pi3K-akt-mTor and inhibiting JNK, P38 MAPK, P38-ERK-JNK, SIRT1, and NF-κB/p53, etc. This paper aims to present the latest progress in research on procatechuic acid, including aspects such as its chemical properties, sources, pharmacokinetics, mechanisms for treating neurodegenerative diseases. Full article

Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, as well as impairments in signaling pathways and gene transcription, which lead to synaptic dysfunction and cognitive decline. Although we are not able to pinpoint the exact differences between healthy aging and neurodegeneration, research increasingly highlights the involvement of neuroinflammation and chronic systemic inflammation (inflammaging) in the development of age-associated impairments via a series of pathogenic cascades, triggered by dysfunctions of the circadian clock, gut dysbiosis, immunosenescence, or impaired cholinergic signaling. In addition, gender differences in the susceptibility and course of neurodegeneration that appear to be mediated by glial cells emphasize the need for future research in this area and an individualized therapeutic approach. Although rejuvenation research is still in its very early infancy, accumulated knowledge on the various signaling pathways involved in promoting cellular senescence opens the perspective of interfering with these pathways and preventing or delaying senescence. Full article

Neurological disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission. Full article

Agastache rugosa, a traditional Asian herbal medicine, is primarily used for digestive problems; yet, its cognitive benefits remain unexplored. This study evaluated the anti-amnesic effects of A. rugosa extract (ARE) on scopolamine (SCO)-induced memory impairment in mice. Mice received 100 or 200 mg/kg ARE orally for 5 days, followed by SCO injection. The ARE demonstrated significant antioxidant (DPPH IC₅₀: 75.3 µg/mL) and anti-inflammatory effects (NO reduction). Furthermore, the ARE significantly improved memory performance in the passive avoidance test (escape latency: 157.2 s vs. 536.9 s), the novel object recognition test (novel object preference: 47.6% vs. 66.3%) and the Morris water maze (time spent in the target quadrant: 30.0% vs. 45.1%). The ARE reduced hippocampal acetylcholinesterase activity (1.8-fold vs. 1.1-fold) while increasing choline acetyltransferase (0.4-fold vs. 1.0-fold) and muscarinic acetylcholine receptor subtype I (0.3-fold vs. 1.6-fold) expression. The ARE improved hippocampal neurogenesis via doublecortin- (0.4-fold vs. 1.1-fold) and KI-67-positive (6.3 vs. 12.0) cells. Therefore, the ARE exerts protective effects against cognitive decline through cholinergic system modulation and antioxidant activity, supporting its potential use as a cognitive enhancer. Full article

Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor—scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated. Full article

Facial nerve injury can cause significant functional impairment, impacting both the peripheral and central nervous systems. The present study evaluated changes in facial motor function, numbers of cholinergic neurons and microglia, and nNOS levels in the facial nucleus of the central nervous system (CNS) following peripheral facial nerve injury. Facial nerve function, as determined by eyeblink and whisker-movement reflexes, was evaluated at baseline and 1, 2, 3, 4, 8, and 12 weeks after inducing facial nerve injury through compression or axotomy. The expression of choline acetyltransferase (ChAT), ionized calcium-binding adaptor molecule 1 (Iba-1), and neuronal nitric oxide synthase (nNOS) in the facial nucleus of the CNS was analyzed 2, 4, and 12 weeks after peripheral facial nerve injury. Compression-induced facial nerve injury was found to lead to temporary facial motor impairment, whereas axotomy resulted in persistent impairment. Moreover, both compression and axotomy reduced ChAT expression and increased Iba-1 and nNOS expression in the facial nucleus, indicating upregulation of an inflammatory response and neurodegeneration. These results indicate that, compared with compression-induced injury, axotomy-induced facial nerve injury results in greater facial motor dysfunction and more persistent microglial and nitric oxide activation in the facial nucleus of the CNS. Full article

Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) that is characterized by systemic immune system activation. This study was performed to assess the alleviative effect of administering an aqueous extract of Eucommia ulmoides leaves (AEEL) on cognitive dysfunction in mice with dextran sulfate sodium (DSS)-induced colitis. The major bioactive compounds of AEEL were identified as a quinic acid derivative, caffeic acid-O-hexoside, and 3-O-caffeoylquinic acid using UPLC Q-TOF/MS^E. AEEL administration alleviated colitis symptoms, which are bodyweight change and colon shortening. Moreover, AEEL administration protected intestinal barrier integrity by increasing the tight junction protein expression levels in colon tissues. Likewise, AEEL improved behavioral dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. Additionally, AEEL improved short-chain fatty acid (SCFA) content in the feces of DSS-induced mice. In addition, AEEL improved damaged cholinergic systems in brain tissue and damaged mitochondrial and antioxidant functions in colon and brain tissues caused by DSS. Also, AEEL protected against DSS-induced cytotoxicity and inflammation in colon and brain tissues by c-Jun N-terminal kinase (JNK) and the toll-like receptor 4 (TLR4) signaling pathway. Therefore, these results suggest that AEEL is a natural material that alleviates DSS-induced cognitive dysfunction with the modulation of gut–brain interaction. Full article