Bezafibrate

Van Hove JLK, et al. Mitochondrion, 2024, 78, 101905.

This case study explores the use of bezafibrate in the treatment of a critically ill infant with pathogenic variants in ACAD9, a gene associated with complex I deficiency. The patient presented with severe lactic acidosis and life-threatening cardiomyopathy, conditions unresponsive to riboflavin therapy, which is commonly used for similar metabolic disorders. Upon administration of high-dose bezafibrate, in combination with nicotinamide riboside, the child showed temporary clinical improvement, including reductions in lactate levels and NT-pro-B-type natriuretic peptide, alongside stabilized echocardiographic measures.
Pharmacokinetic analysis revealed a significant increase in nicotinamide metabolites following treatment, but bezafibrate levels only achieved the active concentration at peak levels, which could explain the limited long-term efficacy of the treatment. Despite these initial positive responses, the patient's condition deteriorated over time, leading to fatal progression of cardiomyopathy and subsequent death at 10.5 months due to cardiac failure complicated by infection.
Proteomic analysis of the patient's blood cells further supported the diagnosis of ACAD9 deficiency, displaying a distinct pattern consistent with this metabolic disorder. Although the treatment regimen, particularly the high-dose bezafibrate, was well tolerated, the weak peroxisome proliferator-activated receptor (PPAR) agonist activity of bezafibrate likely contributed to its suboptimal long-term effectiveness.

Abdalla ZA, et al. Biochemistry and Biophysics Reports, 2023, 36, 101582.

This study investigates the hepatoprotective potential of bezafibrate (BF) when combined with Ginkgo biloba (GKB) extracts in a rat model of doxorubicin (DOX)-induced hepatotoxicity. Doxorubicin, a chemotherapeutic agent, is known to induce liver damage primarily through oxidative stress and inflammatory responses. In this study, rats were administered bezafibrate (100 mg/kg) and Ginkgo biloba extract (60 mg/kg) alone or in combination for 14 days, with doxorubicin administration on days 11-14. The outcomes were compared to a negative control group.
Biochemical analysis revealed that the combination of BF and GKB significantly reduced liver enzymes, including AST, ALP, and the AST/ALT ratio, compared to the single treatments. Additionally, the albumin/globulin ratio and IL-6 levels were significantly lower, indicating reduced inflammation. Notably, oxidative stress markers, such as catalase activity and GSH levels, were markedly elevated in the combination group, further supporting the antioxidative role of the treatment.
Histopathological examination of liver tissue also corroborated the biochemical findings, with the combination treatment demonstrating improved liver architecture and reduced cellular damage compared to both the negative and individual treatment groups. The synergistic effects of bezafibrate and Ginkgo biloba suggest that the combination exerts additive hepatoprotective effects, primarily through anti-inflammatory and antioxidant mechanisms.

Lu Y, et al. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2023, 1869(8), 166841.

This study investigates the neuroprotective effects of Bezafibrate in the 5xFAD transgenic mouse model of Alzheimer's disease (AD). Bezafibrate, a fibrate-class drug traditionally used to regulate lipid metabolism, was evaluated for its ability to rescue mitochondrial dysfunction and other AD-related deficits. The study demonstrated that Bezafibrate was well tolerated by 5xFAD mice and significantly enhanced the expression of key mitochondrial proteins in their brains, thereby improving mitochondrial dynamics and function.
In addition to its effects on mitochondrial function, Bezafibrate treatment notably improved cognitive and memory performance in 5xFAD mice, as measured through behavioral assays. The drug also alleviated amyloid plaque pathology, reduced neuronal loss, and diminished oxidative stress and neuroinflammation in the mouse model. These findings support the hypothesis that enhancing mitochondrial biogenesis and function is a promising therapeutic strategy for AD.
The experimental protocol involved the administration of Bezafibrate (0.5% in diet, approximately 800 mg/kg/day) to 5xFAD mice starting at three months of age for a duration of three months. At six months, the mice were euthanized, and their brains were analyzed for biochemical and immunohistochemical markers associated with mitochondrial function, neuroinflammation, and amyloid pathology. These results underscore the potential of Bezafibrate as a novel neuroprotective agent in AD, particularly by targeting mitochondrial dysfunction and neuroinflammation.

Yang X, et al. Neuropeptides, 2024, 107, 102450.

This study investigates Bezafibrate (BEZ)'s potential therapeutic effects in a TBI mouse model. Mice subjected to TBI were administered BEZ or a vehicle solution, with evaluations focusing on motor and cognitive functions, brain edema, vascular inflammation, blood-brain barrier (BBB) integrity, and tight junction protein expression.
The results reveal that BEZ treatment significantly improved motor and cognitive outcomes in TBI mice, while also reducing brain edema by lowering brain water content. BEZ further alleviated cerebral vascular inflammation, as indicated by suppressed expression of ICAM-1, VCAM-1, and E-selectin. Most notably, BEZ restored the integrity of the BBB, as evidenced by the enhanced expression of the tight junction protein zona occludens 1 (ZO-1). In vitro experiments using TBI-exposed brain endothelial cells (bEnd.3) confirmed these findings, where BEZ mitigated endothelial permeability, restored trans-epithelial electrical resistance (TEER), and increased ZO-1 expression.
Mechanistically, the protective effects of BEZ are attributed to the activation of AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. This suggests that BEZ's neuroprotective actions in TBI are mediated through AMPK signaling, which promotes BBB integrity and reduces neuroinflammation.