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Researchers reveals how certain chemicals protect the brain against cell damage

23.11.2005


Study could lead to better treatments for Alzheimer’s disease



A study by Johns Hopkins scientists has revealed that stimulating brain cell receptors for certain hormone-like chemicals in brain cells called prostaglandins can protect the cells from amyloid â-peptide 42 (Aâ1-42), a compound that has been linked to brain cell death and Alzheimer’s disease (AD).

Prostaglandin E2 (PGE2) is produced via the action of the COX-2 enzyme, which can contribute to brain injury. In spite of the negative effects of COX-2, ongoing studies have shown that PGE2 can actually provide some protection against brain cell death by binding to various PGE2 receptors.


Prostaglandins are a class of compounds that act like hormones by binding to specific receptors. Their many functions include constricting and relaxing blood vessels, controlling clotting, causing pain, and both increasing and decreasing inflammation.

Because neuroinflammation is thought to play a role in the development of AD, PGE2 was a logical place to look for clues to AD toxicity and brain cell death, according to co-lead researcher Sylvain Doré, Ph.D., an associate professor of anesthesiology and critical care medicine and neuroscience at The Johns Hopkins University School of Medicine.

Although it was already known that PGE2 can offer some protection against neurotoxicity, Doré’s study shows that this protection is linked to stimulation of receptors EP2 and EP4. This stimulation results in a cascade of events inside brain cells that produces cyclic-AMP (cAMP), a molecule that protects brain cells by reducing the toxic effects of Aâ1-42.

Doré speculates that the presence of Aâ1-42 in neuritic plaque, a waxy translucent substance consisting of protein and other materials, a hallmark in the brains of AD patients, may cause cellular death by self-assembling into long protein filaments that are toxic to neurons.

It’s also possible, Doré said, that prostaglandin protection works by modifying the link between Aâ1-42 and the overproduction of free radicals. Free radicals are highly reactive chemicals that oxidize other molecules and at high concentrations lead to cell death. Free radicals are associated with neuronal loss observed in AD.

"The development and testing of molecules that can enhance PGE2 receptor activity, and further research into how these receptors increase cAMP concentrations and improve protection could lead to successful new treatments," Doré said.

In the study, published in the European Journal of Neuroscience, Doré and researchers focused on four specific PGE2 receptors, EP1-4, in cortical neuronal cells cultured from postnatal mice.

To establish Aâ1-42-induced neurotoxicity, Doré and his team incubated these neurons with freshly dissolved Aâ1-42 protein for 48 hours. The analysis of the cells showed that Aâ1-42 resulted in a net increase in neuronal cell death compared to control cells that did not receive the peptide.

To investigate the effect of PGE2 on Aâ1-42 toxicity, neurons were co-treated with Aâ1-42 and different concentrations of PGE2. Results showed that PGE2 significantly increased cell survival compared to cultures that received only Aâ1-42.

To determine which of the four PGE2 receptors was responsible in the protection against Aâ1-42 toxicity, Doré’s group conducted three separate experiments. In the first they co-treated neurons with Aâ1-42 and the EP2 agonist butaprost. An agonist is a drug that mimics the action of a natural substance and binds to that substance’s receptor. Results showed that the stimulation of EP2 receptors offered significant protection against Aâ1-42 neurotoxicity.

They also co-treated neurons with Aâ1-42 and the EP4⁄EP3 agonist, OHPGE1, and received similar results.

Conversely, co-treatment of the cells with the EP3⁄EP1 agonist, sulprostone, and Aâ1-42 exhibited no significant protection.

Doré’s group concluded that the protective effects against Aâ1-42 neurotoxicity are specific to PGE2 receptors EP2 and EP4.

The researchers next pursued changes in cAMP levels as a potential underlying cellular mechanism in the protective actions of EP2 and EP4 agonists. They treated neurons with PGE2, butaprost or OHPGE1 for 15 minutes and measured the cAMP concentration inside the cells. Results showed that brief exposure of neurons to PGE2 almost tripled cAMP levels, and exposure to butaprost or OHPGE1 almost doubled them.

Subsequently, to address whether PGE2-mediated neuroprotection involves cAMP, Dore and his group measured neuron toxicity of Aâ1-42 in the absence or presence of cAMP. Treatment with cAMP significantly enhanced cell health after Aâ1-42 exposure indicating that stimulation of PGE2 receptors EP2 and EP4 generates a cascade of events that increases cAMP concentrations and, in turn, reduces Aâ1-42 neurotoxicity.

"Due to the established link between Aâ1-42 and Alzheimer’s disease, this discovery could lead to better drug therapies for treating this disease," Doré said.

Eric Vohr | EurekAlert!
Further information:
http://www.jhmi.edu

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