Neural tissue trauma is a common clinical syndrome with a range of symptoms including paralysis, numbness and pain. Nerve root trauma is a leading cause of radiculopathy from spinal injury, stenosis, or disc herniation. Radiculopathy leads to neck and low back pain, which affects between 12-71% of adults, and imposes high financial burdens. Our rodent model of nerve root compression induces persistent behavioral deficits, Wallerian degeneration, and inflammation at the injury site. Painful root compression induces local and spinal nociceptive and inflammatory changes including altered expression of neuropeptides, growth factors, and cytokines, as well as glial activation, macrophage infiltration, and neuronal hyperexcitability. Despite the clinical prevalence of radiculopathy, effective treatments are still lacking. Flaxseed, a wholegrain that has gained increasing popularity as a health-promoting natural product, has potent antioxidant and anti-inflammatory properties and is rich in the antioxidant lignan secoisolariciresinol diglucoside (SDG). We have shown that dietary SDG formulations boost endogenous antioxidant defenses via induction of the Nrf2 and the Endogenous Antioxidant Response (EAR) pathways and exhibit potent anti-inflammatory activity. The clinical utility of SDG in lignan extract formulations is being confirmed in many clinical studies globally. SDG can cross the blood/brain barrier and enter the CNS, making it an attractive candidate in the context of trauma-induced inflammation. SDG has the potential to promote healing of injured axons, while also modulating the neuroinflammatory cascades known to be involved in oxidative neuronal damage, inflammation, and nociception. We propose to evaluate SDG that is chemically synthesized from vanillin and sugar as a novel biologic agent since extraction methods from the wholegrain have low yield, are prohibitively expensive, and are not capable of generating amounts needed for animal or human testing. Synthetic SDG shares remarkable antioxidant similarities to the natural, extracted SDG. We hypothesize that novel synthetic SDG acts as both a neuroprotective antioxidant and anti-inflammatory agent and mitigates trauma-associated neurotoxicity and inflammation by activating endogenous antioxidant pathways. As such, it is a potential novel biologic therapy facilitating healing in neuronal inflammation/oxidative damage. The major goal of proposed studies is to provide insights into the usefulness of SDG as such an agent and to elucidate its mechanism(s) of action by evaluating inflammation and oxidative cell damage.
Aim 1 investigates the potential mitigating effects of SDG on neural tissue damage and widespread inflammation in an in vivo model using wild type and Nrf2-/- transgenic mice compared to anti-inflammatory NSAID treatment.
Aim 2 uses primary neuronal-glial co-cultures to identify the cellular and biomolecular mechanisms by which SDG modulates EAR activation, glial activation and nociceptive signaling. Studies will identify an important novel biologic therapy with a high degree of potential clinical utility to improve neuronal healing, reduce inflammation and attenuate symptoms after neural trauma.
Trauma and its related syndromes, including paralysis and pain, represent a significant public health problem, and continues to present many clinical challenges due to the fact that current therapeutics have unwanted side-effects and/or are ineffective at treating the constellation of associated pathologies. This proposal seeks to investigate a novel synthetic agent generated from harmless raw materials (vanillin and sugar) with potent anti- inflammatory and antioxidant properties as a potential therapeutic that provides neuroprotection, boosts the endogenous antioxidant defenses and treats pain. Our complementary studies in mouse and culture model systems will identify the mechanistic timing and contributions of pertinent cellular pathways to cell damage and have high potential for developing a novel and effective treatment for this important human health problem.
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