Intracerebral hemorrhage (ICH) is a major public health problem with the highest mortality rate of all stroke subtypes and stroke is the leading cause of long-term adult disability. Since there are no FDA-approved therapies for ICH, it is of enormous importance to establish effective treatments for this medical condition. Following ICH, the deposited blood is damaging to the brain initially by compressing tissue and then by noxious biochemical effects of the hematoma components, including hemoglobin, heme and iron. Our group has found that dimethyl fumarate (DMF), a recently approved oral treatment for multiple sclerosis (MS), with mechanisms associated with activation of the master transcription factor, Nrf2, through a Nrf2-dependent mode of action, provides robust activation of anti-inflammatory, antioxidative, and immunomodulatory responses, reducing edema and neurological dysfunction caused by ICH, in rodent models of ICH with a remarkable 24h therapeutic window. Our central hypothesis is that DMF represents a highly promising novel candidate for the treatment of ICH. The primary objective of this proposal is therefore to develop a safe and optimal oral regimen of DMF for ICH using animal models that simulate clinical risk factors for ICH incidence and severity. These models include advanced age, hypertension, sex differences (to be studied in rats and mice), and larger hematomas in piglets. This design should provide a strong foundation for future clinical studies.
Our specific aims are the following: SA 1: Using a clinically relevant intrastriatal autologous blood injection ICH model in adult male rats, we will develop an optimal, safe, oral regimen of DMF based on effective upregulation of Nrf2-mediated cytoprotective mechanisms in ICH-affected brain, and in peripheral white blood cells of young animals. This paradigm of treatment will result in faster hematoma resolution, reduced cerebral edema, improve long-term recovery, and will not impose any safety concerns. Milestone to transition to R33: a PO regimen that is safe, effectively induces Nrf2 target genes, augments hematoma absorption by 20% at 1 week after injury, and reduces neurological deficits at 4 weeks after injury. SA 2: Using an optimal regimen from SA1, we will define the therapeutic window of DMF vs. placebo PO from 6h to 2d after ICH based upon improvement in neurological deficits at 4 weeks after injury. SA3: We will conduct placebo-controlled studies to determine if DMF reduces long term neurological deficits in female and male aged mice, rats with hypertension, and rats with active bleeding. SA 4: Determine whether DMF will improve outcome compared to vehicle in a piglet model of ICH.
Intracerebral hemorrhage (ICH) is the second most common and deadliest form of stroke. Currently, no effective treatment strategies exist for this devastating disease. The overall goal of this project is to develop DMF, an FDA approved therapy for multiple sclerosis, which we find, through mechanisms involving activation of the transcription factor, Nrf-2, detoxifies blood products, protects against oxidative stress, and reduces inflammation, hematoma size, and neurological disorders. We propose to develop a safe and optimal regimen of DMF in clinically relevant animal models of ICH including aged and hypertensive animals, males and females and in large animals (pig). These studies are crucial to design a future clinical trial of DMF in patients with ICH.
