Multiple sclerosis (MS) is characterized pathologically by inflammation and neurodegeneration. Because current treatments for MS, which are immune modulators, do not prevent neuronal loss and disability, neuroprotective treatments have been sought. Brain derived neurotrophic factor (BDNF) is a phleotrophic cytokine with neuroprotective properties that has been studied as a potential treatment. In an animal model of MS, experimental allergic encephalomyelitis (EAE), BDNF is produced by immune cells and is responsible for reducing axonal loss. BDNF is present in MS lesions and may play a protective role in lesion pathogenesis. Studies of exogenously administered BDNF have been limited by its short serum half-life and poor blood brain barrier (BBB) penetration so we conducted studies using genetically engineered bone marrow stem cells to deliver BDNF in EAE. BDNF reduced inflammation and neurodegeneration and our observations have been confirmed by Linker et al (4) using a lentivirus delivery system. Together these studies suggest that BDNF treatment reduces inflammation and neurodegeneration in EAE. In 2010 Jang et al. reported that 7,8-dihydroxyflavone (DHF) has potent BDNF agonist activity, can be given orally and readily crosses the BBB. In cultured neurons it activated the receptor for BDNF, TrkB, and downstream signaling. It protected wild-type, but not TrkB-deficient neurons from apoptosis. DHF activated TrkB in the mouse brain, inhibited kainic acid-induced neurotoxicity, decreased infarct volumes in experimental murine stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson's disease. Not all DHF effects are TrkB dependent: DHF has anti-inflammatory activity that is NFKB dependent and antioxidant effects that could reduce inflammatory injury. We tested DHF in MOG-induced EAE in C57Bl/6 mice and showed that treatment resulted in reduced clinical and pathological severity even when treatment was delayed until the onset of symptoms. Together these results support further studies of DHF as a possible treatment for MS. Based on the results outlined above, there are at least four possible mechanisms through with DHF could reduce the severity of EAE: It could reduce inflammatory injury through its antioxidant activity, i could reduce inflammation through a non-TrkB mediated pathway, it could reduce inflammation through a TrkB mediated effect on inflammatory cells or it could have a direct TrkB mediated protective effect on neuronal cells. We propose the following Primary Hypothesis: DHF treatment of MOG-induced EAE in C57Bl/6 mice reduces the clinical and pathological severity of disease. We propose the following Secondary Hypothesis: DHF treatment of MOG-induced EAE in C57Bl/6 mice reduces disease severity by a TrkB dependent mechanism. We will test these hypotheses by completing the following specific aims:
Specific Aim #1 : Optimize DHF dosing of C57Bl/6 mice with MOG-induced EAE.
Specific Aim #2 : Determine the effect of DHF treatment started at the time of symptom onset on CNS inflammation, immunity, demyelination, axonal loss and apoptosis in the MOG-induced EAE in C57Bl/6 mice.
Specific Aim #3 : Determine the effect of DHF treatment started on day 50 on CNS inflammation, immunity, demyelination, axonal loss and apoptosis in MOG-induced EAE in C57Bl/6 mice.
Specific Aim #4 : Determine whether the effect of DHF in MOG-induced EAE in C57Bl/6 mice is TrkB dependent by determining the sensitivity of the TrkBF616A knock-in C57Bl/6 mouse to the effects of DHF in mice with and without functioning TrkB. Confirming our hypotheses will provide important new information about the effects of DHF treatment in a model of MS and could provide a rationale for studies of DHF in MS patients.
Multiple sclerosis (MS) is the most common cause of acquired neurological disability in young adults and is a significant cause of disability in veterans. There may be as many as 60,000 veterans suffering with MS, 30,000 seeking care in the VHS for MS and over 6,000 veterans having service connection for MS. The eight approved treatments for MS reduce disease activity and inflammation but do not cure the disease or prevent long term disability. The proposed studies will evaluate a new treatment strategy for MS designed to complement the available treatments and to specifically protect brain cells from permanent damage and stimulate recovery of function. This would represent a major advance in the treatment of veterans with MS.
| Nimmagadda, Vamshi K C; Makar, Tapas K; Chandrasekaran, Krish et al. (2017) SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review. J Neuroimmunol 304:29-34 |
| Gerzanich, Volodymyr; Makar, Tapas K; Guda, Poornachander Reddy et al. (2017) Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis. J Neuroinflammation 14:177 |
| Makar, Tapas K; Nimmagadda, Vamshi K C; Singh, Ishwar S et al. (2016) TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis. J Neuroimmunol 292:9-20 |
| Makar, Tapas K; Gerzanich, Volodymyr; Nimmagadda, Vamshi K C et al. (2015) Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis. J Neuroinflammation 12:210 |
