7 research outputs found
Embryonic Stem Cells Derived Neuron Transplantation Recovery in Models of Parkinsonism in Relation to Severity of the Disorder in Rats
Benfotiamine Treatment Activates the Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase occur in Alzheimer’s disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation, and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in APP/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs, and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigger the expression of Nrf2/ARE- dependent genes in mouse brain as well as in wild-type but not Nrf2-deficient fibroblasts. Active metabolites were more potent in activating the Nrf2 target genes than the parent molecule BFT. Docking studies showed that BFT and its metabolites (but not thiamine) bind to Keap1 with high affinity. These findings demonstrate that BFT activates the Nrf2/ARE pathway and is a promising therapeutic agent for the treatment of diseases with tau pathology, such as AD, frontotemporal dementia, and progressive supranuclear palsy
Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors
Activation of HIF-1alpha and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1alpha and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer\u27s and Parkinson\u27s diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1alpha and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function
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Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease
Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson’s Disease and demonstrated neuroprotective effects
Benfotiamine Treatment Activates Nrf2/ARE Pathway and is Neuroprotective in a Transgenic Mouse Model of Tauopathy
peer reviewedImpaired glucose metabolism, decreased levels of thiamine (vitamin B1) and its phosphate esters, and downregulated activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase have been linked to Alzheimer’s disease (AD). Thiamine-deficient mice exhibit increased amyloid deposition, tau hyperphosphorylation, and oxidative damage1. Experimental evidence has shown that benfotiamine (BFT), a synthetic S-acyl derivative of thiamine, rescued cognitive deficits and reduced amyloid burden in APP/PS1 mice2. We investigated whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) ‒ which causes frontotemporal dementia in humans ‒ in a mouse model of tauopathy. Exposure to BFT resulted in increased lifespan, behavioral improvement, reduced and glycated tau and NFTs, and prevented neuronal death in P301S transgenic (TG) mice. In addition, BFT administration significantly ameliorated mitochondrial dysfunction, attenuated oxidative damage, and decreased the expression of several pro-inflammatory mediators, consistent with a possible activation of the Nrf2/ARE neuroprotective pathway. Accordingly, we found that BFT (but not thiamine) triggers the expression of Nrf2/ARE-dependent genes in wild-type (WT) but not in Nrf2-deficient fibroblasts. Our findings suggest that BFT is a promising therapeutic agent for the treatment of tauopathies