| Mechanism of action of eCB as neuroprotective and neuroregenerative molecules.

| Mechanism of action of eCB as neuroprotective and neuroregenerative molecules.

| Mechanism of action of eCB as neuroprotective and neuroregenerative molecules.

Esther Shohami Ph.D. Raphael Mechoulam Ph.D.

Our studies over the years have demonstrated that the eCB system has the ability to affect the functional outcome after TBI by a variety of mechanisms. The acute, neuroprotective effects are exerted by the eCB within hours and involve inhibition of excitatory neural transmission, inhibition of the inflammatory response and reducing vascular tone. The delayed, neuro-regenerative effects are probably mediated via proliferation of neural progenitor cells. This project aims to explore each of the eCB, CB-like and synthetic analogs that will be tested in-vivo, and proven to be effective in ameliorating the functional outcome after TBI, and which mechanism(s) is involved in affording its effect. Which receptor(s), enzyme(s) and/or signalling pathways are the targets of these molecules, and what sort of interaction with these targets are responsible for mediating the beneficial effect. We will be focusing on each of the multiple components of the neurovascular unit, namely, neurons, astrocytes (and microglia) and the cerebral vasculature, to identify the nature of their specific interaction with the eCB, which appears as a pan-protective system in the CNS, and in the whole body, in general.  (For references see our review in Br J Pharmacol. (11) 163 1402–1410).

 References:

  1. W.A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger and R. Mechoulam.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor.  Science 258, 1946-1949 (1992).
  2. R. Mechoulam et al., Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.  Biochem. Pharmacol. 50, 83-90 (1995).
  3.  D. Panikashvili, C. Simeonidou, S. Ben-Shabat, L. Hanus, A. Breuer,R. Mechoulam and E. Shohami. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury.  Nature  413, 527-531 (2001). 4.
  4. Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E. CB(1) cannabinoid receptors are involved in neuroprotection via NF-kappaB inhibition.. J Cereb Blood Flow Metabol 25, 477-484,  2005.
  5. Panikashvili, D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, and Shohami E.  The endocannabinoid 2-AG protects the blood brain barrier after closed head injury and inhibits expression of proinflammatory cytokines. Neurobiology of Disease, 22, 257-264, 2006.
  6. A. Cohen-Yeshurun, V. Trembovler, A. Alexandrovich, E. Ryberg, P. J. Greasley, R. Mechoulam, E. Shohami, R. R. Leker.  N-Arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J. Cerebral Blood Flow & Metabolism  31, 1768-1777 (2011). 7.
  7. A. Cohen-Yeshurun,  D.Willner, V. Trembovler, A. Alexandrovitch, R. Mechoulam, E. Shohami, R.R.Leker. N-arachidonoyl-L-serine (AraS) possesses proneurogenic properties in vitro and in vivo after traumatic brain injury. J. Cereb Blood Flow  Metab. 33, 1242-1250 (2013).
  8. A. Mann. Endocannabinoid-like entities as neuroprotectants after traumatic brain injury. M.Sc. Thesis (supervisors E. Shohami and R. Mechoulam). 2014.
  9.  E. Shohami, A. Cohen-Yeshurun, L. Magid, M. Elgali,  R. Mechoulam. Endocannabinoids and traumatic brain injury. Br. J. Pharmacol. 163, 1402-1410 (2011).