Scientists at SickKids Kid’s Hospital have discovered that the newly developed molecule LK-2 may lead to the event of recent therapies for brain damage brought on by stroke.

An ischemic stroke occurs when blood flow to a part of the brain is interrupted, depriving brain cells of oxygen and nutrients. Without timely treatment, brain cells can die, leading to everlasting damage to the brain and its functions. Stroke is one in all the leading causes of death and disability worldwide, affecting tens of millions of individuals every year.

A global study published in Nature Co-led by Dr. Lu-Yang Wang, senior scientist within the Neurology and Mental Health program at SickKids, and clinician scientists from Shanghai Jiao Tong University School of Medicine in Shanghai, they found a molecule that has the potential to guard neurons during stroke and stop stroke-related brain damage.

“Our findings provide a very latest way of fascinated about rescuing cells while minimizing the negative uncomfortable side effects of conventional stroke therapy,” says Wang, who holds a Tier 1 Canada Research Chair in Brain Development and Disorders. “The LK-2 molecule could possibly be the important thing to finding an efficient treatment for stroke patients.”

How One Neurotransmitter Contributes to Stroke-Related Brain Damage

Considered one of the essential culprits in stroke-induced brain damage is a neurotransmitter called glutamate. When the brain is deprived of oxygen and sugar, glutamate levels skyrocket, overstimulating N-methyl-D-aspartate receptors (NMDARs) on the membrane of brain cells. This causes a surge in calcium entering the cells, triggering a cascade of events that ultimately result in cell death.

For many years, scientists have tried to develop drugs that may block NMDAR receptors and stop the neurotoxicity related to elevated glutamate levels. Nevertheless, previous drugs targeting NMDAR receptors have been ineffective and haven’t progressed beyond clinical trials, because NMDAR receptors play a crucial role in regular brain functions similar to learning and memory. As well as, blocking NMDAR receptors completely could cause serious uncomfortable side effects, similar to psychosis and cognitive impairment.

The team found that glutamate may also bind to and activate a variety of acidosis sensor called acid-sensing ion channels (ASICs), that are normally activated by acids. ASICs are present within the membrane of brain cells—just like NMDARs—and may allow calcium ions to enter cells once they are stimulated.

“We showed that glutamate can supercharge ASIC activity, especially within the acidic conditions that occur during stroke. Which means that glutamate attacks brain cells through each NMDARs and ASICs—something we didn’t know before.”

Dr. Lu-Yang Wang, Senior Scientist within the Neurology and Mental Health Program at SickKids

A Latest Strategy to Block Excess Glutamate

By identifying the precise site on ASICs where glutamate binds, the team was in a position to develop a latest molecule, called LK-2, that may selectively block the glutamate binding site on ASICs but leave NMDAR receptors unaffected.

In preclinical models, the team found that LK-2 effectively prevented glutamate from overstimulating ASICs, which reduced calcium flux and cell death. Moreover, LK-2 didn’t affect NMDARs or other regular neuronal transmissions, suggesting its potential as a next-generation therapy for stroke.

“Our research has revealed a latest approach to protect the brain from glutamate toxicity without interfering with NMDAR receptors,” Wang says.

Wang’s research will proceed to give attention to investigating the functions and mechanisms of motion of LK-2 with hopes of conducting future clinical trials.

The research team would love to thank Dr. Julie Forman-Kay, senior scientist and head of the Molecular Medicine Program, and Dr. Iva Pritišanac, research associate within the Forman-Kay lab, who assisted Wang in locating glutamate binding sites on ASICs.

Research conducted at SickKids is funded by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Research Chairs Program.