Treatment of neurodegenerative diseases with fenofibrate and analogs thereof
A fenofibrate, neuron technology, applied in the fields of nervous system diseases, neuromuscular system diseases, sensory diseases, etc., can solve the problem of incomplete understanding of the underlying mechanism, and less prevention or treatment of neurodegenerative diseases.
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Embodiment 1
[0056] Fenofibrate is an FDA-approved drug for lowering blood cholesterol levels as a molecule that induces the expression of the PGC-1α gene. In the dopaminergic neuronal cell line MN9D, fenofibrate increased PGC-1α in a dose-dependent manner ( figure 1 on the left side of A) and promotes a smaller increase in mitochondrial content ( figure 1 B). In addition, fenofibrate strongly protected MN9D cells from 6-hydroxydopamine (6-OHDA)-induced oxidative stress-mediated cell death ( figure 1 C). Similarly, fenofibrate also induced the gene expression of PGC-1α in a dose-dependent manner in the microglial cell line BV2 ( figure 2 A) and significantly inhibited LPS-induced up-regulation of IL-Ιβ ( figure 2B). Furthermore, using siRNA to knockdown PGC-1α, fenofibrate-mediated anti-inflammatory effects in BV2 cells were shown to require PGC-1α, which is expressed through the PGC-1α gene ( image 3 A) and II-1β gene expression ( image 3 The reduction of B) is shown. The PPAR...
Embodiment 2
[0062] Fenofibrate crosses the blood-brain barrier and exerts neuroprotective effects on midbrain dopaminergic neurons affected by Parkinson's disease (PD). It is concluded that fenofibrate-mediated upregulation of PGC-1α is safe and effective in the intervention of neurodegenerative diseases (such as PD) associated with PGC-1α deficiency and mitochondrial dysfunction.
[0063] The neuroprotective effect of fenofibrate in mediating PGC-1α upregulation was evaluated in the MPTP toxic mouse PD model. MPTP is a potent neurotoxicant widely used in PD models. MPTP inhibits mitochondrial complex I, induces ROS and causes cell death. There are three main types of MPTP poisoning schemes: acute, subacute, and chronic. There is strong evidence that the 14-day chronic MPTP intraperitoneal infusion regimen more accurately reproduces the pathological features of early stages of PD. Preclinical evaluation of small molecule PGC-1α activators in a chronic MPTP toxicity model is therefore c...
Embodiment 3
[0076]Fenofibrate induces PGC-1α gene expression in the microglial cell line BV2 and inhibits LPS-mediated production of the pro-inflammatory cytokine IL-1β in a dose-dependent manner. Additionally, following siRNA knockdown of PGC-1α, fenofibrate-mediated anti-inflammatory effects in BV2 were shown to require PGC1α. Considering that siRNA only partially knocks down PGC-1α gene expression, using primary CNS cells derived from homozygous and heterozygous PGC-1α knockout mice (PGC-1α- / - and PGC-1α- / +) will provide more definitive evidence that PGC-1α is an indispensable player in mediating the effects of fenofibrate. Heterozygous PGC-1α knockout mice (PGC-1α- / +) were bred (PGC-1α- / +x PGC-1α - / +), and isolate and culture primary microglia hybrids from heterozygous and wild-type neonatal mice. The cells were treated with different concentrations of fenofibrate overnight, followed by incubation with 0.1 ng / mL LPS for 1 hour. Total RNA was isolated and gene expression of the pro-...
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