Microglia, the macrophages that reside in the brain, are believed to be involved in the process of neuronal degeneration in multiple sclerosis and animal models of the disease.  What are the mechanisms by which microglia may be pathological?  A recent report (Shijie et al. Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. Tohuko J Exp Med 2009 Feb;217(2):87-92) suggests that microglial production of glutamate may be a cause of toxicity.

How can glutamate kill neurons?  Glutamate is used by neurons to communicate with each other.  The concentration of glutamate in the brain is tightly controlled by the blood brain barrier, which has specific glutamate transporters to only allow as much glutamate as is needed.  Additionally, when neurons communicate with each other, mechanisms exist to clear up the glutamate very rapidly after the signal is transmitted.  Too much glutamate causes what is called excitotoxicity, that is, death of the neurons from over stimulation.

In the current study the investigators demonstrated that in vitro activated microglial cells produced high concentrations of glutamate, which induced killing of neurons.  Microglial cells were demonstrated to have high concentrations of glutaminase, which generates glutamate.  When glutaminase was inhibited in vitro by addition of a small molecule inhibitor, the ability of the activated microglial cells to make glutamate, and subsequently to kill neurons was decreased. 

Furthermore, it was found that administration of the glutaminase inhibitor to mice suffering from experimental allergic encephalomyelitis (mouse multiple sclerosis) resulted in functional improvement.

These data suggest that microglial toxicity of neurons may be not only related to immunological means, but also through direct production of mediators that kill neurons.

It should be noted that Riluzole, the first drug approved for treatment of ALS works in part through suppressing interacton of glumate with its receptor, as well as upregulating activity of glutamate transporters that clear glutamate.  In fact, Riluzole has actually been demonstrated to inhibit MS-like disease in the EAE model (Gilgun-Sherki et al. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res 2003 Nov 7;989(2):196-204).

Tags: glutamate toxicity, Microglia, multiple sclerosis, riluzole

This entry was posted on Thursday, July 2nd, 2009 at 4:05 am and is filed under Drugs that work in mice, Microglia. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.