Gene expression data from HD mutant and wild type ST14A cells, differentiated for 24 hours and treated with vehicle (DMSO) or with 5M-BM-5M MIND4

ABSTRACT: Activation of cellular responses through the NRF2/KEAP1/ARE pathway is a promising therapeutic strategy to counter neurodegeneration. The present study identified a novel lead compound, MIND4, which induces canonical NRF2-dependent responses and is protective in primary neurons, neuronal slice cultures and a Drosophila model of HuntingtonM-bM-^@M-^Ys disease (HD). In accord with the known anti-inflammatory effects of NRF2 activation, MIND4 and its structural analog, potently repressed an expression of inflammatory markers in activated microglial cells. MIND4 treatment significantly reduced levels of TNF-alpha in the cortex of symptomatic HD mice, demonstrating the neuroprotective anti-inflammatory potential of NRF2 activator in the CNS. A high affinity reversible binding of MIND4 ligands to the NRF2 inhibitor, KEAP1, was identified by a docking model and confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway. The results offer a new therapeutic path for HD and other human diseases. A total of 8 samples, HD mutant and wild type ST14A cells, stably expressing either a mutant expanded repeat (128Q) or wild type (26Q) 546 amino acid huntingtin fragment (a generous gift of E. Cattaneo) (Ehrlich et al., 2001)), 4 HD & 4 control, were used for drug treatment and array-based gene expression analysis. 4 samples, 2 HD and 2 Contol, were treated with 5M-BM-5M MIND4 with each pair ran as replicates. The other 4 samples, 2 HD and 2 Contol, were treated with DMSO with each pair ran as replicates.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Leslie Thompson 

PROVIDER: E-GEOD-49392 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress