Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 16, 2022

Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue cell functions significant increases the risks of various aging-related diseases, including neurodegenerative cardiovascular metabolic musculoskeletal immune system diseases. Although development modern medicine has promoted human health greatly extended life expectancy, aging society, variety chronic diseases have gradually become most important causes disability death elderly individuals. Current research on focuses elucidating how endogenous exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss proteostasis, compromise autophagy, mitochondrial cellular senescence, stem exhaustion, altered intercellular communication, deregulated nutrient sensing) participate regulation aging. Furthermore, thorough pathogenesis to identify interventions that promote longevity caloric restriction, microbiota transplantation, nutritional intervention) clinical treatment methods for (depletion senescent cells, therapy, antioxidative anti-inflammatory treatments, hormone replacement therapy) could decrease incidence turn healthy longevity.

Language: Английский

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An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders

CNS Drugs, Journal Year: 2024, Volume and Issue: 38(4), P. 239 - 254

Published: March 19, 2024

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence DRBA exposure. Recommendations for anticholinergic in patients DIMDs were developed on the basis roundtable discussion healthcare professionals extensive expertise DIMD management, along comprehensive literature review. agreed that "extrapyramidal symptoms" non-specific term encompasses range abnormal movements. As such, it contributes to misconception all can be treated same way, leading misuse overprescribing anticholinergics. neurobiologically clinically distinct, different treatment paradigms varying levels evidence use. Whereas indicates anticholinergics effective DIP they not recommended TD, or NMS; nor supported preventing except individuals at high risk acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) central impaired cognition), which highly concerning especially older adults. Appropriate therefore requires careful consideration efficacy supportive but TD) risks events. If used, medications should prescribed lowest dose limited periods time. When discontinued, tapered gradually.

Language: Английский

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Benefits and limitations of nanomedicine treatment of brain cancers and age-dependent neurodegenerative disorders

Seminars in Cancer Biology, Journal Year: 2022, Volume and Issue: 86, P. 805 - 833

Published: June 30, 2022

Language: Английский

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Immunity orchestrates a bridge in gut-brain axis of neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 85, P. 101857 - 101857

Published: Jan. 17, 2023

Language: Английский

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Advancing age and sex modulate antidyskinetic efficacy of striatal CaV1.3 gene therapy in a rat model of Parkinson’s disease

Neurobiology of Aging, Journal Year: 2025, Volume and Issue: 149, P. 54 - 66

Published: Feb. 20, 2025

We previously demonstrated that viral vector-mediated striatal CaV1.3 calcium channel downregulation in young adult (3mo) male parkinsonian rats provides uniform, robust protection against levodopa-induced dyskinesias (LID). Acknowledging the association of PD with aging and incidence female sexes, we have expanded our studies to include advancing age both sexes. The current study directly contrasts sex, determining their impact on efficacy intrastriatal AAV-CaV1.3-shRNA prevent LID induction, removing variable levodopa-priming. Considering sexes together, late-middle-aged ('aged'; 15mo) receiving developed significantly less severe compared control AAV-scramble(SCR)-shRNA rats, however therapeutic benefit was than observed males. When considered separately, females showed Furthermore, aged non-cycling/proestrous-negative were refractory regardless vector. This novel insight into sex antidyskinetic responses CaV1.3-targeted gene therapy, highlighting importance including clinically relevant populations studies.

Language: Английский

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Cholinergic interneuron inhibition potentiates corticostriatal transmission in direct medium spiny neurons and rescues motor learning in parkinsonism

Cell Reports, Journal Year: 2022, Volume and Issue: 40(1), P. 111034 - 111034

Published: July 1, 2022

Striatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them learning and action selection. This pause is lost animal models of Parkinson's disease. How this signal regulates the striatal network remains an open question. Here, we examine impact CIN firing inhibition on glutamatergic transmission between cortex medium spiny neurons expressing dopamine D1 receptor (D1 MSNs). Brief interruption activity has no effect control conditions, whereas it increases responses MSNs denervation. potentiation depends upon M4 muscarinic protein kinase A. Decreasing by optogenetics/chemogenetics vivo partially rescues long-term motor deficits parkinsonian mice. Our findings demonstrate that exerted CINs corticostriatal striatal-dependent motor-skill integrity dopaminergic inputs.

Language: Английский

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D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(8), P. 1693 - 1706

Published: May 9, 2022

ABSTRACT Background In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating therapeutic options scarce. Aberrant activity striatal cholinergic interneurons (SCIN) has been shown to be critical PD dyskinesia, but the systemic administration medications can exacerbate extrastriatal‐related symptoms. Thus, targeting mechanisms causing pathological SCIN in severe with is a promising alternative. Methods We used ex vivo electrophysiological recordings combined pharmacology study alterations intracellular signaling that contribute altered physiology observed 6‐hydroxydopamine mouse model treated levodopa. Results The phenotypes parkinsonian mice during “off levodopa” state resulting from aberrant Kir/leak Kv1.3 currents rapidly reverted by acute inhibition cAMP‐ERK1/2 signaling. Inverse agonists inhibit ligand‐independent D5 receptors, like clozapine, restore normal dyskinetic mice. Conclusion Our work unravels pathway involved dysregulation membrane hyperexcitability burst‐pause levodopa ( l ‐dopa). These changes persist off‐medication periods due tonic acutely reversed pharmacological interventions. D5‐cAMP‐ERK1/2 selectively may have effects restoring function. © 2022 International Parkinson Movement Disorder Society.

Language: Английский

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Adenosine A2A antagonists and Parkinson’s disease

International review of neurobiology, Journal Year: 2023, Volume and Issue: unknown, P. 105 - 119

Published: Jan. 1, 2023

Language: Английский

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Radiomics and Hybrid Models Based on Machine Learning to Predict Levodopa-Induced Dyskinesia of Parkinson’s Disease in the First 6 Years of Levodopa Treatment

Diagnostics, Journal Year: 2023, Volume and Issue: 13(15), P. 2511 - 2511

Published: July 27, 2023

Background: Current research on the prediction of movement complications associated with levodopa therapy in Parkinson’s disease (PD) is limited. levodopa-induced dyskinesia (LID) a complication that seriously affects life quality PD patients. One-third patients develop LID within 1 to 6 years treatment. This study aimed construct models based radiomics and machine learning predict early PD. Methods: We extracted features from T1-weighted MRI obtained baseline 49 control 54 first therapy. Six brain regions related onset were segmented as interest (ROIs). The least absolute shrinkage selection operator (LASSO) was used for feature selection. Using methods support vector (SVM), random forest (RF), AdaBoost, we constructed hybrid models. combined Unified Disease Rating Scale part III (UPDRS III) total score. five-fold cross-validation performed repeated 20 times validate stability classifiers. sensitivity, specificity, accuracy, receiver operating characteristic (ROC) curves, area under ROC curve (AUC) model validation. Results: selected 33 out 6138 features. In testing set model, AUC values SVM, RF, AdaBoost classifiers 0.905, 0.808, 0.778, respectively, accuracies 0.839, 0.742, 0.710. had better performance. set, 0.958, 0.861, 0.832, 0.903, 0.806, 0.774. Conclusions: Our results indicate valuable predicting work demonstrates combination clinical has good potential value identifying

Language: Английский

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Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l -DOPA–induced dyskinetic behaviors

Science Advances, Journal Year: 2024, Volume and Issue: 10(47)

Published: Nov. 20, 2024

A dynamic equilibrium between dopamine and acetylcholine (ACh) is essential for striatal circuitry motor function, as imbalances are associated with Parkinson’s disease (PD) levodopa-induced dyskinesia (LID). Conventional theories posit that cholinergic signaling pathologically elevated in PD a result of increased ACh release, which contributes to deficits. However, using approaches measure receptor-mediated signaling, we found that, rather than the predicted enhancement, strength transmission at muscarinic M4 receptor synapses on direct pathway medium spiny neurons was decreased dopamine-depleted mice. This adaptation due reduced postsynaptic resulting from down-regulated receptors downstream signaling. Restoring unexpectedly led partial alleviation deficits LID dyskinetic behavior, revealing an unexpected prokinetic effect addition canonical antikinetic role receptors. These findings indicate function differentially parkinsonian pathophysiology, representing promising target therapeutic intervention.

Language: Английский

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