Prospects of antidiabetic drugs in the treatment of neurodegenerative disease DOI Creative Commons
Lidan Hu, Wenmin Wang, Xiangjun Chen

et al.

Brain‐X, Journal Year: 2024, Volume and Issue: 2(1)

Published: Feb. 29, 2024

Abstract Neurodegenerative diseases (NDs) stand for a group of disorders characterized by the progressive loss neurons in brain and peripheral organs, resulting motor cognitive dysfunction. The global prevalence NDs, including Alzheimer's disease, Parkinson's Huntington's amyotrophic lateral sclerosis, is on rise globally, primarily due to an aging population, positioning NDs as increasing significant public health concern. Despite intensive research, few effective therapies that prevent or delay ND progression have been developed. Mounting evidence indicates one well‐defined risk factors type 2 diabetes mellitus, insulin resistance has also proven be related decline. Certain antidiabetic drugs, such glucagon‐like peptide‐1 receptor agonists, peroxisome proliferator‐activated gamma metformin, shown promise offering neuroprotective benefits alleviating symptoms beyond their glucose‐lowering effects. Although exact mechanisms remain elusive, these drugs offer promising novel strategy managing disorders. In this review, we first highlight specific effects multiple discuss main action treating NDs. These include reducing protein aggregation improving apoptosis, mitochondrial dysfunction, oxidative stress, neuroinflammation. Finally, summarize clinical trials evaluating

Language: Английский

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases DOI Creative Commons
Jian Sheng Loh, Wen Qi Mak, Li Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

Citations

255
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

173
The benefits of GLP-1 drugs beyond obesity DOI
Daniel J. Drucker

Science, Journal Year: 2024, Volume and Issue: 385(6706), P. 258 - 260

Published: July 18, 2024

Glucagon-like peptide–1–based medicines have weight loss–independent actions

Language: Английский

Citations

51
Exosomes as therapeutic and drug delivery vehicle for neurodegenerative diseases DOI Creative Commons
Zeinab Nouri, Ashkan Barfar,

Sahra Perseh

et al.

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 2, 2024

Abstract Neurodegenerative disorders are complex, progressive, and life-threatening. They cause mortality disability for millions of people worldwide. Appropriate treatment neurodegenerative diseases (NDs) is still clinically lacking due to the presence blood-brain barrier (BBB). Developing an effective transport system that can cross BBB enhance therapeutic effect neuroprotective agents has been a major challenge NDs. Exosomes endogenous nano-sized vesicles naturally carry biomolecular cargoes. Many studies have indicated exosome content, particularly microRNAs (miRNAs), possess biological activities by targeting several signaling pathways involved in apoptosis, inflammation, autophagy, oxidative stress. Exosome content influence cellular function healthy or pathological ways. Furthermore, since exosomes reflect features parental cells, their cargoes offer opportunities early diagnosis intervention diseases. unique characteristics make them ideal delivering drugs directly brain. These include ability pass through BBB, biocompatibility, stability, innate properties. This review emphasizes role alleviating NDs discusses associated molecular mechanisms. exosomes, making promising natural transporter various medications brain combat NDs, also discussed.

Language: Английский

Citations

30
12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study DOI Creative Commons
Riccardo De Giorgi, Ivan Koychev, Amanda Adler

et al.

EClinicalMedicine, Journal Year: 2024, Volume and Issue: 74, P. 102726 - 102726

Published: July 10, 2024

SummaryBackgroundWhile semaglutide, approved for type-2 diabetes mellitus (T2DM), is being investigated as a treatment brain disorders, concerns over adverse neuropsychiatric events have emerged. More data are therefore needed to assess the effects of semaglutide on health. This study provides robust estimates risk neurological and psychiatric outcomes following use compared three other antidiabetic medications.MethodsThis retrospective cohort used electronic health records from TriNetX US Collaborative Network, covering >100 million patients in USA. Due exploratory nature this study, we did not pre-registered protocol or statistical analysis plan. Three cohorts with T2DM prescribed between 1st December 2017 31st May 2021 were propensity-score matched (1:1 using greedy nearest-neighbour algorithm calliper distance 0.1) receiving sitagliptin, empagliflozin, glipizide. Using Cox regression analysis, risks 22 within one year since index prescription: encephalitis, parkinsonism, cognitive deficit, dementia, epilepsy/seizure, migraine, insomnia, nerve disorder, myoneural junction/muscle disease, intracranial haemorrhage, ischaemic stroke, alcohol misuse, opioid cannabis stimulants nicotine psychosis, bipolar depression, anxiety, obsessive-compulsive suicidality. Negative control (NCOs) unmeasured confounding.FindingsEach included 23,386 (semaglutide vs sitagliptin), 22,584 (vs empagliflozin), 19,206 glipizide) patients. Semaglutide was associated an increased outcomes. Instead, after multiple-testing correction, reduced several such outcomes, notably deficit sitagliptin (HR 0.72, 95% CI 0.64–0.80) glipizide 0.63–0.81), dementia 0.52, 0.40–0.68), misuse across most comparisons 0.61–0.85 against glipizide; HR 0.77, 0.65–0.90 empagliflozin; 0.82, 0.70–0.95 though latter no longer statistically significant adjustment multiple comparisons). Empagliflozin showed fewest differences semaglutide. No NCOs observed cohorts.InterpretationSemaglutide higher 12-month medications. Potential beneficial associations some especially should stimulate validation clinical trials.FundingNational Institute Health Research (NIHR) Oxford Biomedical Centre, Medical Council.

Language: Английский

Citations

18
GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias DOI
Huilin Tang, William T. Donahoo, Steven T. DeKosky

et al.

JAMA Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Importance The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) risk of Alzheimer disease related dementias (ADRD) remains to be confirmed. Objective To assess the ADRD associated with GLP-1RAs SGLT2is in people type 2 diabetes (T2D). Design, Setting, Participants This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium January 2014 June 2023. Patients were 50 years or older T2D no prior diagnosis antidementia treatment. Among 396 963 eligible patients T2D, 33 858 included GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 SGLT2i GLD 24 117 cohort. Exposures Initiation treatment a GLP-1RA, SGLT2i, second-line GLD. Main Outcomes Measures was identified using clinical codes. Hazard ratios (HRs) 95% CIs estimated Cox proportional hazard regression models inverse probability weighting (IPTW) adjust for potential confounders. Results cohort (mean age, 65 years; 53.1% female), 65.8 49.3% 63.8 51.7% female). In IPTW-weighted cohorts, incidence rate lower initiators compared (rate difference [RD], −2.26 per 1000 person-years [95% CI, −2.88 −1.64]), yielding an HR 0.67 (95% 0.47-0.96). had than (RD, −3.05 −3.68 −2.42]), 0.57 0.43-0.75). There SGLT2is, RD −0.09 −0.80 0.63) 0.97 0.72-1.32). Conclusion Relevance both statistically significantly decreased GLDs, observed drugs.

Language: Английский

Citations

2
State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease DOI Creative Commons
Elizabeth M. Rhea,

Manon Leclerc,

Hussein N. Yassine

et al.

Aging and Disease, Journal Year: 2023, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2023

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance a key feature of most forms T2DM has been investigated for over century, research on brain (BIR) more recently developed, including the context non-diabetes states. Recent data support presence BIR aging brain, even states, found that may be Alzheimer’s disease (AD) contributes to cognitive impairment. Further, therapies used treat are now being AD treatment prevention, insulin. In this review, we offer definition BIR, present evidence AD; discuss expression, function, activation receptor (INSR) brain; how could develop; tools study BIR; correlates current hallmarks; regional/cellular involvement BIR. We close discussion resilience both AD, can improved better understand future avenues research. Overall, review position paper highlights as plausible therapeutic target prevention decline dementia due AD.

Language: Английский

Citations

35
The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson’s Disease Pathogenesis DOI Open Access
Viviana A. Ruiz‐Pozo, Rafael Tamayo‐Trujillo, Santiago Cadena-Ullauri

et al.

Nutrients, Journal Year: 2023, Volume and Issue: 15(16), P. 3585 - 3585

Published: Aug. 15, 2023

Parkinson’s disease (PD) is a degenerative condition resulting from the loss of dopaminergic neurons. This neuronal leads to motor and non-motor neurological symptoms. Most PD cases are idiopathic, no cure available. Recently, it has been proposed that insulin resistance (IR) could be central factor in development. IR associated with neuropathological features like α-synuclein aggregation, loss, neuroinflammation, mitochondrial dysfunction, autophagy. These related impaired metabolism, death, aggravation Moreover, pharmacological options involve signaling improvement non-dopaminergic strategies have under drugs prevent metabolic pathways involved damage. All these approaches improve outcomes. Also, new biomarker identification may allow for an earlier diagnosis high-risk individuals. review describes main implicated development involving IR. presents several therapeutic directed at used treatment. The understanding molecular mechanisms neurodegenerative enhance diagnosis.

Language: Английский

Citations

29
Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases DOI Creative Commons
Elizabeth M. Rhea,

Alice Babin,

P. C. Thomas

et al.

Tissue Barriers, Journal Year: 2023, Volume and Issue: 12(4)

Published: Dec. 14, 2023

Background A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's (PD). Transport across the blood–brain barrier (BBB) is one way IRAs to act directly within brain. To determine which are high priority candidates treating these disorders, we have studied their brain uptake pharmacokinetics.

Language: Английский

Citations

27
Increased intestinal bile acid absorption contributes to age-related cognitive impairment DOI Creative Commons
Zhenxing Ren, Ling Zhao,

Mingliang Zhao

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(5), P. 101543 - 101543

Published: May 1, 2024

Cognitive impairment in the elderly is associated with alterations bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary acids (CPBAs) and ammonia individuals, mild cognitive impairment, Alzheimer's disease, aging rodents, a more pronounced change females. These changes are correlated increased expression ileal apical sodium-bile transporter (ASBT), hippocampal synapse loss, brain CPBA rodents. vitro experiments confirm that CPBA, taurocholic acid, induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates impact on as well decline Additionally, administration an sequestrant, cholestyramine, alleviates normalizing CPBAs mice. findings highlight potential targeting absorption therapeutic strategy for age-related impairment.

Language: Английский

Citations

17