Researchers have described a new mechanism to explain the effects of subcortical strokes and a new possible therapeutic approach. Their findings suggest that an excessive amount of GABA, an inhibitory neurotransmitter, from reactive astrocytes accounts for cortical glucose hypometabolism followed by subcortical stroke. It also impedes rehabilitation-aided motor functional recovery by aberrantly suppressing motor cortical neuronal activity. Thus, this pathway, and the enzyme that synthesizes GABA, could be a therapeutic target for functional recovery after subcortical stroke.

The work is published in Cell Reports in the article, “Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke.

Stroke is one of the most commonly reported causes of death and greatly impacts patients’ quality of life. A stroke occurs when the blood supply is interrupted or reduced due to bleeding or occlusion of blood vessels in some part of the brain. Brain cells subsequently begin to die within minutes, causing regional brain damage.

The stroke leads to a loss of function, known as diaschisis, in other brain regions connected to the damaged area. Diaschisis worsens the symptoms and prognosis of stroke patients. However, despite the broad clinical interest, diaschisis’ molecular and cellular mechanisms are still unknown.

In addition, the authors noted that glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. Here too, the molecular and cellular mechanisms have been poorly elucidated.

In this study, the researchers reported that diaschisis in the cortex of the mouse brain with subcortical stroke is caused by the decline of neuronal activity, due to the reduction in neuronal glucose uptake. They showed that this is dependent on pathological changes of astrocytes, the most abundant cell type in the brain.

“Astrocytes respond to the presence of any chemical disregulation, caused by stroke. They become reactive, proliferate, and increase in size,” said C. Justin Lee, PhD, director of the Cognitive Glioscience Group at the IBS Center for Cognition and Sociality in Daejeon, Korea.

The researchers discovered that reactive astrocytes synthesize and release an excessive amount of GABA, an inhibitory neurotransmitter, that affects the activity of neighboring motor neurons.

Using an animal model, the authors showed that GABA-synthesizing reactive astrocytes in distant cortical areas “cause glucose hypometabolism via tonic inhibition of neighboring neurons.”

They also demonstrated that the diaschisis is significantly alleviated by the treatment with KDS2010, which efficiently blocks astrocytic GABA synthesis by inhibiting MAO-B, one of the key enzymes in the production of GABA. KDS2010 is currently licensed out to the pharmaceutical company, Neurobiogen.

The authors wrote that “reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism.”

They further reported that rehabilitation training of the animals with stroke was not effective to recover the motor function. However, the treatment with KDS2010 accompanied by rehabilitation training dramatically mitigated the motor impairment due to the stroke.

“Our findings demonstrate that astrocytic GABA-mediated cortical diaschisis impedes functional recovery after white matter stroke,” explained Min-Ho Nam, MD, PhD, researcher at the Korea Institute of Science and Technology (KIST) and first author of the study.

“Diaschisis is observed in migraine, glioblastoma, and traumatic brain injury, in addition to stroke. This study will provide a novel therapeutic approach for those diseases as well,” added Hyoung-Ihl Kim, MD, PhD, researcher at Gwangju Institute of Science and Technology (GIST) and co-corresponding author of the study.

In conclusion, the researchers’ data indicate that “cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.” And, the authors suggest that blocking astrocytic GABA synthesis with KDS2010 alleviates cortical diaschisis and stimulates rehabilitation-aided functional recovery in white matter stroke.

Stroke affects not only the brain areas where the blood supply is interrupted or reduced (infarct), but also other distal areas (diaschisis). The researchers studied mouse brains and found that diaschisis is due to the excessive production of the neurotransmitter GABA and that the administration of KDS2010 combined with rehabilitation can improve motor function after stroke. [IBS]

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