New Small Molecule AZ67 May Help Prevent Brain Cell Death, Early Data Show

A small molecule that alters glucose metabolism in stressed brain cells may help prevent their death, representing a new strategy for treating brain diseases including amyotrophic lateral sclerosis, Alzheimer’s disease, and Huntington’s disease, among others.

The potential therapeutic candidate was described in the journal Scientific Reports in a study titled, “Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice.”

Most cells in the body extract energy from sugar, or glucose molecules, through a process called glycolysis. In contrast, brain nerve cells usually do not rely on this process; instead, they use mechanisms or even rely on neighboring cells to get the energy they need.

But there is an exception: When there is damage to the brain as a result of stroke or disease, some neurons will perform glycolysis. This process is regulated by a protein called PFKFB3, which acts as a “master activator” that “turns on” glycolysis in neurons. However, this change in behavior results in cellular stress, and can ultimately lead to cell death.

Researchers from Gero Discovery, a pharmaceutical company specializing in PFKFB3 inhibitors, in collaboration with the Institute of Biomedical Research of Salamanca and Nanosyn, tested a new small molecule called AZ67 for its ability to block the activity of PFKFB3 and protect neurons from glycolysis-mediated death.

Through a battery of lab experiments, the team first demonstrated that AZ67 can effectively inhibit PFKFB3 activity and reduce glycolysis-induced cellular stress in neurons cultured in dishes.

Next, they tested the new compound in a mouse model of stroke. Mice were treated with AZ67 or a placebo immediately following brain injury induced by stroke, and the animals were evaluated the following day.

Mice treated with placebo showed severe neurological damage, with average Neurological Severity Scores (NSSs) above 3, motor coordination of about 40% that of mice without strokes, and 43% percent (by volume) of the mice’s brains showing signs of damage. In contrast, mice treated with AZ67 had average NSSs of about 2, retained 60% motor coordination, and 27% brain volume affected, suggesting significantly less neurological damage than the other group.

Researchers also administrated AZ67 to mice that were healthy and had not had strokes to further assess the impact of the treatment. In general, the brains of these mice appeared unaffected, suggesting relatively low toxicity of AZ67. Still, additional studies are warranted to assess potential toxicity before the compound is approved for human testing.

“These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy in excitotoxic-related disorders such as stroke [and neurological illnesses],” the team concluded.

“We are glad that our hypothesis that pharmacological inhibition of PFKFB3 can be beneficial in an excitotoxicity-related condition such as stroke was confirmed,” Olga Burmistrova, director of preclinical development at Gero Discovery and a co-author of the study, said in a press release.

“These promising results bring hope to dozens of millions of patients suffering from life-threatening neurological diseases,” said Maksim Kholin, Gero Discovery’s co-founder and business development director.