The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases.

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.

Is type 2 diabetes associated dementia a microvascular early-Alzheimer's phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?

There is increasing evidence of a positive association of type 2 diabetes with Alzheimer's disease (AD), the most prevalent form of dementia. Suggested pathways include cerebral vascular dysfunction; central insulin resistance, or exaggerated brain abundance of potentially cytotoxic amyloid-ß (Aß), a hallmark feature of AD. However, contemporary studies find that Aß is secreted in the periphery by lipogenic organs and secreted as nascent triglyceride-rich lipoproteins (TRL's). Pre-clinical models show that exaggerated abundance in blood of TRL-Aß compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Aß moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Aß by peripheral lipogenic organs attenuates the early-AD phenotype indicated in animal models, consistent with causality. Poorly controlled type 2 diabetes commonly features hypertriglyceridemia because of exaggerated TRL secretion and reduced rates of catabolism. Alzheimer's in diabetes may therefore be a consequence of heightened abundance in blood of lipoprotein-Aß and accelerated breakdown of the BBB. This review reconciles the prevailing dogma of amyloid associated cytotoxicity as a primary risk factor in late-onset AD, with substantial evidence of a microvascular axis for dementia-in-diabetes. Consideration of potentially relevant pharmacotherapies to treat insulin resistance, dyslipidaemia and by extension plasma amyloidemia in type 2 diabetes are discussed.

Circulatory disturbance of the cochlear spiral modiolar artery in a type 2 diabetic mouse model.

Objective: This study aimed to identify significant differences in cochlea microvessel size between a diabetic mouse model (db/db) and normal mice using three-dimensional (3D) quantitative analysis. Methods: Six control heterozygote db/+ as well as 18 male B6/BKS(D)-Leprdb/J (db/db) mice aged 14 (n = 9) and 28 (n = 9) weeks were examined. After clearing the cochlea, we reconstructed the 3D volumes of the spiral modiolar artery (SMA) in the cochlea using light-sheet microscopy and analyzed vessel wall thickness, cross-sectional area, short and long diameter, and vessel height. Results: The average SMA-wall thickness in the db/db-mouse group (3.418 ± 0.328 µm) was greater than that in the control group (2.388 ± 0.411 µm). The average cross-sectional outer area, short diameter, and long diameter of the SMA in db/db mice were significantly larger than those in control mice (all p < 0.001). The cross-sectional areas increased with age (control: 221.782 ± 121.230 µm, 14 weeks; 294.378 ± 151.008 µm, and 28 weeks; 312.925 ± 147.943 µm). Conclusion: The db/db mice had thicker and larger proximal-SMA vessel walls and diameters than control mice, respectively, thus potentially inducing increased blood viscosity or vascular insufficiency and aggravating hearing loss in type 2 diabetes mellitus. Level of Evidence: IIb.

Aged garlic extract as a potential prophylactic to reduce the progression of endometriosis and associated pain burden.

Endometriosis is a complex and potentially debilitating condition that has major impact on quality of life. There is emerging evidence that biological compounds found in garlic (Allium sativum) may be effective for attenuating endometrial pain. Suggested mechanisms for efficacy include modulation of inflammation and potent antioxidant effects. Aged-garlic-extract (AGE) is a centuries old process describing ethanolic extracts of garlic bulbs for 12-20 months. The AGE formulation realised contains a complex array of stabilised biologics with significant immunomodulatory effects relevant to inflammatory conditions. This perspective article puts forward a hypothesis that AGE should be considered as a prophylactic to manage endometrial pain.