Therapeutic strategies for acute brain injury

Background:

Finding ways to improve outcome following acute injury to the brain, such as a stroke, continues to prove challenging. One approach is to identify potential candidates from those drugs either already in use or in human trials for other purposes. Part of the rationale being that such a strategy should hasten candidate drugs into clinical trial.

In addition, this laboratory has set out to identify drugs that offer not only neuroprotection but also activate endogenous repair processes in the brain and thereby stimulate neurorestoration. There is an increase in the rate of neurogenesis after a stroke, both in rodent and human brain. While in some cases it appears that new neurons can differentiate appropriately, the efficiency of this response is limited because many of these newborn cells do not survive.

Previous work from the laboratory focused on progesterone and G-CSF (Granulocyte Colony Stimulating Factor), which is now in extended Phase II trials for acute stroke. Progesterone is an attractive stroke therapeutic as it is inexpensive, sold by generic companies for chronic and not acute use, and readily available. We suspect that part/all of the benefits of progesterone result from its metabolism in the brain. More recently we have begun to assess the therapeutic value of inhibitors of histone deacetylases (HDACs), which are well-advanced in clinical trials for cancer. These drugs have an acute neuroprotective effect on the existing complement of mature neurons and can drive neural progenitor cells towards adopting a "neuronal" phenotype.

Current Projects:

• administration of progesterone and various metabolites
• inhibition of specific HDACs

• sensitization to brain antigens following stroke (Kyra Becker)
  
• role of Fca/mR in microglial activation during cerebral ischemia (Thomas Moeller)
  
• role of miR-155 in ischemic brain injury (Thomas Moeller)
  
• effect of ischemic preconditioning on the microglial transcriptome (Jon Weinstein)

Research Methods:

The laboratory utilizes a wide variety of in vivo and in vitro approaches including; experimental mouse models of stroke and trauma, behavioral testing, imaging, cell and molecular biology techniques.

Bibliography:

SELECTED PUBLISHED AND ACCEPTED ARTICLES IN REFEREED JOURNALS:

Gibson, C.L., Bath, P.M.W. and Murphy, S. (2005) G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 25: 431-439.

Gibson, C.L., Jones, N.C., Prior, M.J.W., Bath, P.M.W. and Murphy, S. (2005) G-CSF suppresses edema formation and reduces IL-1_ expression following cerebral ischemia in mice. J. Neuropathol. Exp. Neurol. 64: 763-769.

Gibson, C.L., Constantin, D.C., Prior, M.J.W., Bath, P.M.W. and Murphy,S. (2005) Progesterone suppresses the inflammatory response and NOS-2 expression following cerebral ischemia. Exp. Neurol. 193: 522-530.

Gibson, C.L., Coughlan, T. and Murphy, S. (2005) Glial nitric oxide and ischemia. Glia. 50: 417-426.

Jones, N.C., Constantin, D., Prior, M.J.W., Morris, P.G., Marsden, C.A. and Murphy, S. (2005) The neuroprotective effect of progesterone after traumatic brain injury in male mice is independent of both the inflammatory response and growth factor expression. Eur. J. Neurosci. 21: 1547-1554.

Jones, N.C., Prior, M.J.W., Burden-Teh, E., Marsden, C.A., Morris, P.G. and Murphy, S. (2005) Antagonism of the interleukin-1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2 positive cells and improves anatomical and functional outcomes. Eur. J. Neurosci. 22: 72-78.

Willmot, M., Gray, L., Gibson, C.L., Murphy, S. and Bath, P.M.W. (2005) A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide: Biol. Chem. 12: 141-149.

Willmot, M., Gibson, C.L., Gray, L., Murphy, S. and Bath, P.M.W. (2005) Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow; a systematic review. Free Rad. Biol. Med. 39: 412-425.

Coughlan, T., Gibson, C.L. and Murphy S. (2005) Modulatory effects of progesterone on iNOS expression in vivo and in vitro. J. Neurochem. 93: 932-942.
Murphy, S. and Pearce, B.R. (2005) Second messenger systems. In: Neuroglia 2nd Edition (H. Kettenmann and B.R. Ransom, eds.), pp 216-228. Oxford University Press.

Murphy, S. (2005) Free radicals and EAE. In: Experimental Models of Multiple Sclerosis (E. Lavi and C.S. Constantinescu, eds.), Springer.

Constantinescu, C.S., Tani, M., Ransohoff, R.M., Wysocka, M., Hilliard, B., Fujioka, T., Murphy, S., Tighe, P.J., Trinchieri, G. and Rostami, A. (2005) Astrocytes as antigen presenting cells: expression of IL-12/IL23. J. Neurochem. 95: 331-340.

Gibson, C.L., Gray, L., Murphy, S. and Bath, P.M.W. (2006) Estrogen and experimental ischemic stroke: a systematic review. J. Cereb. Blood Flow Metab. 26: 1103-1113.

Murphy, S. and Coughlan, T. (2006) Nitric oxide synthases in brain function. In: Handbook of Neurochemistry and Molecular Neurobiology 3rd edition (A. Lajtha, ed.) Vol. 9 Neuroactive proteins and peptides (R. Lim, ed.), Springer. pp 223-242.

Murphy, S. and Gibson, C.L. (2007) Nitric oxide, ischemia and brain inflammation. Biochem. Soc. Trans. 35: 1133-1137.

Sun, Y., Alexander, S.P.H., Garle, M.J., Gibson, C.L., Hewitt, K., Murphy, S.P., Kendall, D.A. and Bennett, A.J. (2007) Cannabinoid activation of PPARα; a novel neuroprotective mechanism. Brit. J. Pharmacol. 152, 734-743.

Gibson, C.L., Gray, L., Bath, P.M.W. and Murphy, S. (2008) Progesterone for the treatment of experimental brain injury; a systematic review. Brain 131, 318-328.