healthinnovations, neurodegeneration, neuroinflammation, neuroinnovations, neuroprotection, opensource, stroke

Novel neuroprotector successfully reduces brain damage after stroke in preclinical studies.

After suffering a stroke, which is estimated to kill more than 6 million people annually, about three-quarters of patients exhibit some disability.  It is known that most strokes occur when a disruption of blood flow prevents oxygen and glucose from reaching brain tissue, ultimately killing neurons and other cells. Therefore, the extent of a patient’s symptoms depends on the degree and location of brain tissue damage following the stroke event.  Now, researchers at the University of Nebraska-Lincoln and the National University of Singapore have developed a molecule that can inhibit an enzyme linked with the onset of stroke that appeared to reduce the inflammation that typically accompanies it.  The team state that its molecule, known as 6S, reduced the death of brain tissue by as much as 66 percent when administered to the cerebrum of a rat that had recently suffered a stroke.  The opensource study is published in the journal ACS Central Science.

Previous studies show that the gaseous neuromodulator hydrogen sulfide (H2S) is associated with neuronal cell death pursuant to a stroke. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke.  After a stroke, levels of H2S appear to be elevated, leading to brain tissue damage, however, the details of how that happens are still a bit of a mystery.  The current study develops a quick way to synthesize molecules deduced to inhibit the production of H2S.

The current study modelled the inhibitor on a naturally occurring molecule produced by the CBS enzyme, tailoring the molecule’s structure to improve its performance. Results show that by swapping out functional groups of atoms known as amines with hydrazines, increased the inhibitor’s binding time from less than a second to hours.  Data findings show in vitro that these compounds block CBS from making H2S by mimicking one of its other products.

Results show a 70% reduction in the severity of stroke damage in rats when the compound was injected an hour after the simulation of a stroke.  The group explain that their inhibitor works by binding to CBS, an enzyme that normally helps regulate cellular function which can also trigger production of toxic levels of H2S in the brain. They go on to state that they wanted a compound that would bind well to this enzyme and that could be synthesized easily.  They conclude that the fact that this inhibitor remained effective when given as post-stroke treatment is encouraging, as this is the norm in the treatment of acute stroke.

The team surmise that because their 6S inhibitor has demonstrated its effects in cell cultures and the brain tissue of rats, it represents just an initial step toward developing a stroke-treating drug for humans. They go on to add, however, the proof-of-principle experiments effectively illustrate the concept’s promise.  For the future, the researchers state that using molecules like the ones they made will help the global medical community dissect the mechanism underlying H2S-mediated neuronal damage and will serve as an important starting point for the development of even more drug-like compounds that act in a similar manner.

Source: University of Nebraska-Lincoln

 

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (l,l)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine–imine interchange. It is demonstrated that the most potent “zipped” inhibitor 6S reduces H2S production in SH-SY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; ∼70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia. “Zipped Synthesis” by Cross-Metathesis Provides a Cystathionine β-Synthase Inhibitor that Attenuates Cellular H2S Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model. Berkowitz et al 2016.
The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (l,l)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine–imine interchange. It is demonstrated that the most potent “zipped” inhibitor 6S reduces H2S production in SH-SY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; ∼70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia. “Zipped Synthesis” by Cross-Metathesis Provides a Cystathionine β-Synthase Inhibitor that Attenuates Cellular H2S Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model. Berkowitz et al 2016.

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