Sterol biosynthesis disruption by common prescription medications: critical implications for neural development and brain health

Brain medicine :, Год журнала: 2025, Номер unknown, С. 1 - 6

Опубликована: Фев. 25, 2025

Sterol biosynthesis is essential for cellular function, producing not only cholesterol but also critical bioactive molecules that regulate cell signaling, growth, and membrane function. In the brain, metabolism operates independently behind blood–brain barrier, maintaining its own homeostatic balance. An emerging concern in clinical pharmacology discovery many common prescription drugs unintentionally interfere with post-lanosterol sterol synthesis pathways. While acute effects of these medications are documented, their long-term consequences brain development function remain unclear. Studies using cultures mouse models indicate heightened risk during pregnancy, where drug-induced disruption may interact genetic factors from both mother fetus, particularly when multiple prescribed. This significant research gap has important implications practice. Our review consolidates current evidence about how affect outlines areas requiring urgent investigation.

Язык: Английский

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Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation

Journal of Xenobiotics, Год журнала: 2025, Номер 15(2), С. 44 - 44

Опубликована: Март 14, 2025

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and progression of neurodegenerative diseases. The brain’s complex architecture, composed interconnected cell types receptors, drives unique neuronal signaling pathways, modulates enzyme functions, leads to distinct CYP gene expression regulation patterns compared liver. Despite their relatively low levels expression, CYPs exert significant influence on responses, neurotoxin susceptibility, behavior, neurological disease risk. These are essential maintaining homeostasis, mediating cholesterol turnover, synthesizing metabolizing neurochemicals, neurosteroids, neurotransmitters. Moreover, they key participants oxidative stress neuroprotection, inflammation. In addition roles psychotropic drugs, substances abuse, endogenous compounds, impact efficacy, safety, resistance, underscoring importance beyond traditional metabolism. Their involvement critical physiological processes also links them onset Understanding cerebral is vital advancing neuroprotective strategies, personalizing treatments disorders, developing CNS-targeting therapeutics. This review explores emerging enzymes, particularly those within CYP1–3 CYP46 families, highlighting functional diversity pathological consequences dysregulation health. It examines potential CYP-based biomarkers improve diagnosis treatment offering new avenues therapeutic innovation.

Язык: Английский

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Commonly prescribed multi‐medication therapies exert sex‐specific effects on Alzheimer's disease pathology and metabolomic profiles in App^NL‐G‐F mice: Implications for personalized therapeutics in aging

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(3)

Опубликована: Март 1, 2025

Abstract INTRODUCTION Polypharmacy is common among older adults and people with dementia. Multi‐medication therapy poses risks of harm but also targets comorbidities risk factors associated dementia, offering therapeutic potential. METHODS We evaluated the effects two polypharmacy regimens monotherapies on male female App NL‐G‐F knock‐in mice. assessed functional, emotional, cognitive outcomes;amyloid pathology; serum metabolomics profiles. RESULTS A combination metoprolol, simvastatin, aspirin, paracetamol, citalopram improved memory, reduced amyloid burden neuroinflammation, modulated AD‐associated metabolomic signatures in mice, negligible Substituting cardiovascular drugs impacted emotional domains worsened predominantly In males, could not explain effects, suggesting drug synergy, whereas certain monotherapy were lost when combined. DISCUSSION This study uncovers sex‐specific an AD model, identifying mechanisms biomarkers that can guide gender‐specific use medicines dementia prevention management. Highlights Two combinations show pathology Metoprolol+simvastatin+aspirin+paracetamol+citalopram improves memory Replacing metoprolol simvastatin enalapril atorvastatin eliminates benefits mice impairs Selected produce only partially outcomes combinations. Metabolomic pathways indicate possible for evaluating effectiveness safety personalized therapies aging

Язык: Английский

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Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer’s astrocytes

Alzheimer s Research & Therapy, Год журнала: 2024, Номер 16(1)

Опубликована: Март 23, 2024

Abstract Alzheimer’s disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject great interest. The mainstream theory AD pathology suggests that primarily associated with tau protein amyloid-beta (Aβ). However, an increasing body research has revealed abnormalities in lipid metabolism may be important event throughout pathophysiology AD. Astrocytes, as members network brain, play significant role this event. study abnormal astrocytes provides new perspective for understanding pathogenesis This review focuses on fatty acids (FAs) cholesterol AD, discusses it from three perspectives: uptake, intracellular breakdown or synthesis metabolism, efflux transport. We found that, despite accumulation their own acids, cannot efficiently uptake neurons, leading to acid within neurons resulting lipotoxicity. In terms exhibit decrease endogenous due exogenous cholesterol. Through thorough investigation these metabolic abnormalities, we can provide insights future therapeutic strategies by literature navigate complex maze bring hope patients disease.

Язык: Английский

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Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

European Journal of Neuroscience, Год журнала: 2024, Номер 60(1), С. 3466 - 3490

Опубликована: Май 10, 2024

Abstract In females, Alzheimer's disease (AD) incidences increases as compared to males due estrogen deficiency after menopause. Estrogen therapy is the mainstay for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. plays crucial role amyloid precursor protein (APP) processing overall neuronal health by regulating various factors such brain‐derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain‐associated (Daxx) translocation, glutamatergic excitotoxicity, Voltage‐Dependent Anion Channel, Insulin‐Like Growth Factor 1 Receptor, estrogen‐metabolising enzymes apolipoprotein E (ApoE) polymorphisms. All these impact physiology of postmenopausal women. replacement therapies play an important treatment strategy prevent However, use may lead increased risks breast cancer, venous thromboembolism cardiovascular disease. Various therapeutic approaches have used mitigate effects on AD. These include therapy, Selective Receptor Modulators (SERMs), Beta (ERβ)‐Selective Agonists, Transdermal Delivery, Localised Combination Therapies, Metabolism Modulation Alternative Estrogenic Compounds like genistein from soy, notable phytoestrogen plant sources. mechanism via which modulate women not explained earlier thoroughly. Present review will enlighten all molecular mechanisms Along‐with this, association between estrogen, ApoE polymorphisms also be discussed

Язык: Английский

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Sex, senescence, senolytics, and cognition

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Март 4, 2025

This review focuses on sexual dimorphism in cellular senescence and senolytic treatment relation to brain health age-related cognitive decline. The stressors of aging, DNA damage, inflammation, oxidative stress induce cell senescence, a hallmark aging. Senescent cells change their function molecular profile are primed release pro-inflammatory cytokines. functional changes include the activation signals prevent death. cytokines from peripheral senescent during middle age induces neighbor heightens level systemic contributing neuroinflammation. In response neuroinflammation stress, some neurons alter physiology, decreasing neuronal excitability synaptic transmission. neurophysiology is protective against death due excitotoxicity, at expense loss normal function, inflammation may underlie prevalence, symptoms, pathogenesis diseases, including neurodegenerative diseases. Sex differences have been observed for astrocytes, microglia, cells, those involved innate adaptive immune responses. Interventions that remove such as drugs, can reduce or ameliorate aging-related function. Similarities responses males females depend system examined, regimen, burden, when initiated. Estrogen impacts several these factors influences transcription genes promoting growth, proliferation, survival programs manner opposite drugs. addition, estrogen has anti-aging effects independent rapidly modifying neurophysiology. Thus, it important recognize that, addition sex there other sexually dimorphic mechanisms contribute aging process. results indicate senolytics interact with fundamental biology, hormones.

Язык: Английский

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The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson’s disease

PLoS Biology, Год журнала: 2025, Номер 23(2), С. e3002974 - e3002974

Опубликована: Фев. 18, 2025

Parkinson’s disease (PD) is a neurodegenerative characterized by the death of dopaminergic neurons in substantia nigra and formation Lewy bodies that are composed aggregated α-synuclein (α-Syn). However, factors regulate α-Syn pathology nigrostriatal degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), brain-specific oxysterol catalyzed CYP46A1, elevated cerebrospinal fluid PD patients. Herein, we show levels CYP46A1 24-OHC patients increase with age mouse model. Overexpression intensifies pathology, whereas genetic removal attenuates neurotoxicity brain. supplementation exogenous exacerbates mitochondrial dysfunction induced fibrils. Intracerebral injection enhances spread neurodegeneration via X-box binding protein 1 (XBP1) lymphocyte-activation gene 3 (LAG3) levels. Thus, promote XBP1–LAG3 axis. Strategies aimed at inhibiting CYP46A1-24-OHC axis LAG3 could hold promise as disease-modifying therapies

Язык: Английский

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Why women may be more prone to Alzheimer’s disease

Aging Brain, Год журнала: 2024, Номер 6, С. 100121 - 100121

Опубликована: Янв. 1, 2024

Язык: Английский

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Lipid metabolism in Alzheimer’s disease

Aging Research, Год журнала: 2024, Номер 2(2), С. 9340037 - 9340037

Опубликована: Июнь 1, 2024

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