New drugs can be treated with double pens

Stroke victims face cruel clocks – Treatment of symptoms must begin within hours of symptoms onset, or the death of millions of brain cells.

But researchers at Metropolitan University of Osaka have developed a drug that even if given drugs that protect mice from stroke damage six hours after initial injury could extend a critical therapeutic window that could save countless lives.

An experimental compound called GAI-17 targets a rogue protein during stroke, forming toxic clumps that kill brain cells. The study, published in Iscience, shows how this protein aggregation can be prevented in a mouse model of acute ischemic stroke, thus greatly reducing brain damage and paralysis, the most common type affecting 87% of stroke patients.

When good proteins are spoiled

The culprit, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) usually helps cells produce energy. But during stroke, oxygen deprivation and subsequent blood rushing to brain tissue (called ischemia-reperfusion injury) can create huge oxidative stress.

Under these harsh conditions, GAPDH molecules begin to stick together through chemical bonds formed by key amino acids called cysteine-152. These protein clumps then invade the powerful chamber of cells, causing them to malfunction and eventually lead to cell death.

Principal investigator Nakajima is Nakajima, and found that GAPDH clustering occurs before brain tissue actually dies, suggesting that this may be the cause, not just the result of stroke injury. His team confirmed this using transgenic mice that expressed a mutated version of GAPDH of the anticoagulant.

Double tube attack stroke attack

The researchers used genetic and drug methods to test their hypotheses:

• Genetic protection: Mice designed to produce antipolymerized GAPDH show 45% stroke injury
• Drug intervention: GAI-17 treatment can reduce brain damage and improve neurological function through similar amounts
• Extended window: This drug remains effective 3-6 hours after the stroke
• Target delivery: Fluorescence tracking shows GAI-17 enters neurons specifically, not other brain cells

What is particularly promising about Gai-17 is its specificity. Triamino acid peptides (serine-cysteine thiosine) bind near sites where GAPDH is easily aggregated without interfering with the normal energy-generating function of the protein.

Compete with time

Current stroke treatments face severe time limits. The clot-damaged drug TPA must be given within 4.5 hours, while the mechanical clot removal procedure has a 6-hour window. Many patients arrive late at the hospital, and these interventions are too late for doctors to have few choices.

The 6-hour potency window of GAI-17 may have the potential to help more patients, although it still cannot address the delay in health care in many cases. The researchers found that when treatment started nine hours after it started, there was no benefit, suggesting how long can biological limitations save brain cells.

Importantly, GAI-17 has no side effects on heart rate, blood pressure, or cerebral blood flow (a critical safety factor for stroke treatment). The drug also did not interfere with the essential metabolic function of GAPDH by cellular energy production measurements.

From the laboratory bench to the bedside

The team developed GAI-17 through a systematic test of 21 different peptide sequences, evaluating the sequence of each peptide to prevent GAPDH from agglomerating without toxic effects. They used computer modeling to understand how the winning compound binds to the GAPDH surface near the problematic cysteine 152 residue.

However, the current form of GAI-17 faces practical challenges for human use. The peptides decompose rapidly in the blood and need to be directly injected into these experiments. The researchers noted that they have developed a more stable version of small molecules that can be given systematically although these results are awaiting publication.

Beyond stroke

GAPDH aggregation is not unique to stroke. The same process occurs in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases where oxidative stress can damage brain cells. This suggests that GAI-17 or similar compounds may have a wider therapeutic application.

This study uses increasing awareness to drive many brain diseases by driving protein aggregation. With the conditions caused by mutations in a single gene, stroke and neurodegeneration are usually caused by a normally-acting protein until the pressure pushes it to the harmful configuration.

While there is hope, this work has limitations. This study used only one type of stroke model in young healthy mice. The real stroke may vary in older patients with multiple medical conditions. The researchers also focused on the acute phase, leaving questions about long-term welfare.

Nevertheless, these findings offer hope for an expanded stroke treatment regimen. As Nakajima notes, developing drugs targeting the fundamental cellular damage mechanisms can provide “single treatments for many tricky neurological diseases”, a goal that seems impossible just a few decades ago.

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