NRF2/ARE PATHWAY AS A THERAPEUTIC TARGET FOR AMYOTROPHIC LATERAL SCLEROSIS

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DESCRIPTION (provided by applicant): Pathological activation of oxidative damage, neuroinflammation, and mitochondrial dysfunction are implicated in pathogenesis of Amyotrophic lateral sclerosis (ALS). These pathophysiolgical aspects are tightly regulated by Nrf2/ARE (NF-E2 related factor 2/antioxidant response element) signaling, the impairment of which triggers detrimental signaling events leading to motor neuron death in ALS. Due to this, the Nrf2/ARE pathway is considered important and has great promise to be explored for neurotherapeutics in neurodegenerative diseases such as ALS. The Nrf2 has been identified as a key regulatory factor in the coordinated induction of ARE driven "battery" of neuroprotective genes; e.g. antioxidant and anti-inflammatory proteins. The Nrf2 system is regulated by the cytosolic protein Keap1 (Kelch like ECH associated protein 1) that binds to Nrf2 and prevents its translocation to the nucleus. Oxidation of a critical cysteine in Keap 1 allows Nrf2 to translocate into the nucleus, where it activates transcription of a large number of genes encoding phase II detoxification enzymes. Our synthetic triterpenoids, are structurally modified to achieve increased bioavailability in central nervous system and are potent activators of Nrf2/ARE pathway. Oral administration of these Nrf2/ARE activators in ALS mice resulted in translocation of Nrf2 from cytoplasm to nucleus and upregulated expression of genes involved in antioxidant response and mitochondrial biogenesis while pro-inflammatory genes were downregulated in ALS mice. In pilot experiments in G93A SOD1 mice, treatment with these triterpenoids resulted in decrease in weight loss, improvement in motor performance and most importantly a significant increase in survival. We hypothesize that Nrf2/ARE signaling pathway is impaired in ALS and synthetic triterpenoids possess great potential as therapeutic candidates in preventing motor neuron death. Two specific aims are proposed to test our hypothesis. In aim 1, we will examine the efficacy of triterpenoid drugs CDDO (2-cyano-3, 12- dioxooleana-1,9-dien-28-oic acid) ethylamide, and CDDO-trifluoroethylamide in blocking motor deficits, neuronal loss, oxidative damage and inflammation in a mouse model of ALS when triterpenoids are administered during symptomatic and presymptomatic stages. This will enable us to validate and identify the most potent triterpenoid in preventing ALS-like disease in mice. In aim 2, we will determine the targets downstream of the Nrf2/ARE modulated by the most potent triterpenoid drug in an effort to identify the precise neuroprotective mechanism of action in a mouse model of ALS. Unraveling the neuroprotective mechanisms modulated by these synthetic triterpenoids through activation of Nrf2/ARE signaling pathway will enable us to develop these compounds into potential therapeutic drugs to retard the death of motor neurons in ALS. PUBLIC HEALTH RELEVANCE: This study proposes to examine the role of Nrf2/ARE pathway in Amyotrophic Lateral Sclerosis (ALS). The long-term goal is to understand the role of Nrf2/ARE genetic program in ALS and to determine the neuroprotective efficacy of synthetic triterpenoids that activate the neuroprotective Nrf2/ARE signaling pathway in motor neurons in the mouse model of ALS. The study will enable us to characterize Nrf2/ARE pathway and to determine the best synthetic triterpenoid as a potential drug candidate for the development of an effective therapeutic strategy for ALS.