Promising Test Molecule Shows Potential to Reverse Neurological Damage Caused by Stroke

Introduction to Stroke and Its Impact

Stroke is a major contributor to global mortality and morbidity. In 2013, it ranked as the second leading cause of death worldwide and the third leading cause of disability. The severe impact of stroke is partly due to the unclear mechanisms behind the neurological damage it causes.

Understanding the Mechanism of Ischaemic Stroke

A recent study published in the journal *Scientific Reports* investigates a hypothesis regarding how ischaemic stroke leads to neuron death and examines a specific molecule that may halt this process. The proposed mechanism centers around glucose metabolism. Human cells primarily utilize glucose as an energy source, but nerve cells prefer a different metabolic pathway known as the Pentose Phosphate Pathway (PPP). This pathway is advantageous for neurons as it reduces oxidative by-products that can cause cell death.

The Role of APC/C-Cdh1 in Neuron Metabolism

The enzyme APC/C-Cdh1 plays a critical role in directing neurons towards the PPP instead of glycolysis by inhibiting PFKFB3, another enzyme. Previous findings indicate that APC/C-Cdh1 is inhibited during a stroke, leading to increased glycolytic activity and subsequent neuronal damage due to accumulated oxidative by-products.

Research Focus: AZ67 Molecule

This study explores the potential of a molecule named AZ67, which targets PFKFB3. The objective was to determine whether AZ67 could effectively inhibit this enzyme and thereby mitigate the effects of ischaemic stroke.

Methodology and Findings

The research team began by testing AZ67 in vitro, measuring the enzyme activity of PFKFB3 with and without the presence of the molecule. They observed that AZ67 successfully inhibited the enzyme’s activity in a dose-dependent manner.

To assess AZ67’s effects on live neurons, the team utilized neuron cell cultures from genetically modified mice that produced human PFKFB3. AZ67 was found to be non-toxic at the tested concentrations while continuing to inhibit PFKFB3 effectively.

Mechanism of Action Exploration

To further investigate the mechanism, researchers introduced a stabilizing substance for PFKFB3, which led to increased neuron cell death. This effect was counteracted by AZ67, demonstrating its protective role. Additionally, when APC/C-Cdh1 was inhibited, resulting in increased PFKFB3 activity and neuron death, AZ67 again reversed this outcome.

The study also compared the effects of AZ67 on neurons with naturally low PFKFB3 levels versus astrocytes, which have higher levels. The results suggested that AZ67 specifically inhibits glycolysis in neurons without affecting astrocytes, confirming the proposed mechanism.

Impact on Motor Skills

In vivo experiments showed that AZ67 could reduce the loss of motor skills following an ischaemic stroke simulation in mice. Treated mice experienced significantly less impairment in motor skills compared to control mice.

Implications and Future Directions

This study achieves three significant outcomes: it elucidates the cellular mechanisms leading to neuron death in stroke, identifies a potential therapeutic target in AZ67, and provides substantial evidence through both in vitro and in vivo experiments. While AZ67 represents a promising avenue for treatment, it faces numerous challenges before advancing to large-scale clinical trials. Nonetheless, the findings highlight potential new treatment strategies for addressing stroke-related neurological damage.

References

Feigin VL, Norrving B, Mensah GA. Global Burden of Stroke. Circ Res. 2017;120(3):439-48.
Burmistrova O, Olias-Arjona A, Lapresa R, Jimenez-Blasco D, Eremeeva T, Shishov D, et al. Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice. Sci Rep. 2019;9(1):11670.