Molecular cabal contributes to stroke damage

November 22, 2005

In the neural train wreck that is stroke, the cutoff of oxygen kills brain cells through a buildup of acid, as well as by overexciting receptors on the surface of brain cells. Now, researchers exploring the detailed mechanism of this excitotoxicity and acidotoxicity have discovered how an insidious chain of molecular events contributes to its damage. In an article in the November 23, 2005, issue of Neuron, Jun Gao and colleagues say that their findings could contribute to the development of drugs to protect against the molecular "cabal" that produces such lethality.

In their experiments, the researchers discovered the molecular mechanism linking two key components of neuronal damage due to oxygen starvation, or ischemia. One component is a type of receptor called an NMDA receptor (NMDAR). This receptor is triggered by glutamate, which is known to be released during ischemia.

The other component of neuronal damage that they studied is an "acid-sensing ion channel," (ASIC)--basically, a pore-like protein in the membranes of neurons. In response to the acid unleashed by ischemia, ASICs open to admit calcium into the cell, and calcium overload is central to neuronal death.

In their experiments, Gao and colleagues induced ischemia in rat brains, or deprived cultured neurons of oxygen, and analyzed the molecular effects. Their analyses revealed that such deprivation triggered NMDARs, which in turn activated an important cell switch called CaMKII. This enzyme, they found, acts on a particular ASIC, called ASIC1a, to greatly enhance its sensitivity to the acid induced by ischemia. This increased sensitivity causes the ASIC channel to open and flood the neuron with lethal doses of calcium.

Importantly, the researchers found in cultures of neurons that drugs that inhibited NMDAR or CaMKII prevented the ischemia-induced enhancement of ASIC sensitivity, as well as neuronal death.

"In summary, our report provides a functional linkage between NMDAR-mediated exitotoxicity and ASIC-mediated acidotoxicity induced by ischemia, which is known to cause excessive glutamate release and acidosis. Both NMDARs and [calcium permeable] ASICs have now been implicated in ischemic neuronal damage.

"Our finding...sheds new light on the development of therapeutic agents against excitotoxic and acidotoxic neuronal damage," concluded the researchers. Also, they added, since such NMDARs and ASIC1a are involved in seizures and pain sensation, "a similar coupling between these two channels is likely to occur in these diseases as well."
-end-
The researchers include Jun Gao, Bo Duan, De-Guang Wang and Tian-Le Xu of the Chinese Academy of Sciences in Shanghai, China and the University of Science and Technology of China in Hefei, China; Xiao-Hong Deng and Lin Xu of the Chinese Academy of Sciences in Shanghai, China; Guang-Yi Zhang of Xuzhou Medical College in Xuzhou, China. This research was supported by the National Natural Science Foundation of China (Nos. Grants 30125015, 30321002), the National Basic Research Program of China (No. 2006CB500803), and the Knowledge Innovation Projects from the Chinese Academy of Sciences (KSCX 2-SW-217). J.G. is supported by the China Postdoctoral Science Foundation and the K.C. Wong Education Foundation.

Gao et al.: "Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death." Publishing in Neuron, Vol. 48, 635-646, November 23, 2005, DOI 10.1016/j.neuron.2005.10.011, www.neuron.org

Cell Press

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.