An international collaboration led by a team at the Hospital for Sick Children (SickKids), Toronto, has developed a new molecule that shows promise to protect neurons during stroke and prevent stroke-related damage.
The study, published today in Nature, details the characteristics of the newly created molecule, called LK-2, which targets the activity of glutamate, a neurotransmitter that has previously been identified as one of the main culprits behind brain cell damage and death during stroke. The new molecule takes a different approach to stroke treatment.
In ischemic stroke, blood flow to a part of the brain is interrupted which deprives brain cells of the oxygen and nutrients it needs to survive. When the brain is deprived of oxygen and sugar, the levels of glutamate in the brain rise dramatically which results in the overstimulation of N-methyl-D-aspartate receptors (NMDARs) on the membrane of brain cells. This results in a surge of calcium entering cells leading to a cascade of events resulting in cell death.
NMDARs have long been a target of drug developers looking to develop stroke treatments. But attempts to block NMDARs in order to prevent the neurotoxicity caused by excess glutamate have been unsuccessful, largely because NMDARs also play an important role in normal brain functions that include memory and learning. Blocking NMDAR activity can completely lead to side effects that include psychosis and cognitive impairment.
In this new work, co-led by Lu-Yang Wang, a senior scientist in the neurosciences and mental health program at SickKids, and clinician scientists at the Shanghai Jiao Tong University School of Medicine, the team discovered that acid-sensing ion channels (ASICs), which normally are activated by acid, also play an important role in ischemic stroke. Glutamate also binds to ASICs which, like NMDARs, are present in the membrane of brain cells and can allow calcium ions into the brain when stimulated.
“We have shown that glutamate can supercharge the activity of ASICs, especially under the acidic conditions that occur during stroke,” Wang said. “This means that glutamate is attacking brain cells through both NMDARs and ASICs—something we did not know before now.”
The researchers were able to identify the specific site in ASICs where glutamate binds and used that knowledge to develop LK-2 which can selectively block that specific binding.
Studying the effects of LK-2 in preclinical models, the team noted that it effectively prevented the overstimulation of ASICs by glutamate, which reduced the flow of calcium to cells, preventing cell death. In addition, LK-2 did not have any effect on other regular neural transmissions or NMDARs—allowing them to provide their normal activities in the brain.
“Our findings provide an entirely new way to think about saving cells while minimizing the adverse neural side effects of conventional stroke therapy,” noted Wang. “The LK-2 molecule could be the key to unlocking successful therapeutics for stroke patients.”
Wang and his team are continuing their work with LK-2 in the hopes of developing a clinical trial that could lead the molecule to becoming a new form of stroke treatment.
