Stroke Therapy
Drown out the molecular "distress signal" from dead neurons
Every year in our country, about half a million people are overtaken by a stroke – an extremely dangerous, life-threatening condition caused by an acute violation of cerebral circulation, which often leads to irreversible death of nerve cells. Many molecules are usually involved in the processes of cell death, and recently scientists have found new molecular targets, exposure to which can reduce the degree of brain damage in stroke.
Article by Chen et al. Farnesyl pyrophosphate is a new danger signal inducing acute cell death published in the journal PLOS Biology.
The cells of our body are constantly dying. Some – with a "planned" replacement, others – by "violent" means in various pathological conditions, such as inflammation, insufficient blood supply, toxicosis, etc.
Unlike programmed cell death (apoptosis), with pathological death (necrosis), the cell membrane ruptures and its contents come out. So in the microenvironment of the dead cell there are molecules that work as "beacons" that recruit immune cells responsible for inflammation to the "scene of the incident", and thus trigger processes leading to further cell death.
Recently, Chinese scientists have discovered a substance that, in high extracellular concentrations, triggers the mass death of neurons in stroke – an acute violation of the blood supply to the brain. This molecule turned out to be farnesyl pyrophosphate, an intermediate product of the so–called mevalonate pathway for the synthesis of biologically active compounds such as steroids (for example, cholesterol). The high cytotoxic effect of farnesyl pyrophosphate is provided by its structure – a negatively charged phosphate "head" and a long 15-carbon hydrophobic "tail".
Farnesyl pyrophosphate is usually present in the extracellular space in a small and quite "safe" amount, but during a stroke everything changes, because the mevalonate pathway is very active in neurons. And when many cells die at the same time, and their "remains" are not diluted with circulating blood, this powerful "distress signal" can become a serious threat to the patient's life.
In laboratory mice with narrowing of the middle cerebral artery, an animal model of ischemic brain injury, the researchers proved an increase in the level of farnesyl pyrophosphate in tissues with deterioration of cerebral blood flow. After investigating this phenomenon in experiments on cell cultures, they found that the disastrous effect of farnesyl pyrophosphate can be prevented if the concentration of extracellular calcium is lowered. These results suggest that farnesyl pyrophosphate promotes the opening of one of the types of cell channels that regulate the intake of calcium ions, and their excessive activity leads the cell to death.
Scientists have found that it is possible to reduce the degree of damage to brain tissue by preliminary administration of a calcium channel blocker or compounds that inhibit the synthesis of farnesyl pyrophosphate. Among such substances were already known drugs: zoledronic acid, used in the treatment of osteoporosis, as well as simvastatin for the correction of elevated cholesterol levels.
So, new targets have been discovered in the therapy of brain tissues damaged by ischemic stroke. But before the introduction of this method into practice, there is still a lot to learn, for example, what is the duration of the temporary "window" when such an intervention can benefit. And in any case, due to the complex nature of ischemic damage, this method will only complement a number of already known methods of stroke treatment.
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