A group of scientists and clinicians from the Cologne, Mainz, and Münster have discovered a completely new approach to the treatment of stroke: they were able to demonstrate that a specific signaling pathway of lysophosphate acid (LPA), a bioactive lipid in the brain, regulates the excitability of nerve cells after a stroke and thus influences the severity of the impairment in those affected. This LPA signaling pathway is controlled by the enzyme autotaxin (ATX). In the experimental model, inhibition of ATX was shown to reduce the excitability of networks in the brain even hours after stroke. This resulted in the consequences of the stroke being less severe. The results of the studies have now been published in "Science Translational Medicine".
In a stroke triggered by a vascular occlusion (ischemic stroke), there is an insufficient supply of blood and thus also an insufficient supply of oxygen and nutrients to the brain. As a result, large amounts of neurotransmitters are released in the brain. In particular, the excessive release of the neurotransmitter glutamate causes an overstimulation of the brain cells. This can lead to a dysfunction of nerve cells and their death. As a further consequence, brain tissue is permanently lost, which in turn can cause permanent disabilities.
Currently, stroke treatments aim to save functionally impaired but still viable tissue. This is done by correcting the circulatory disturbance as early as possible with medication or catheter treatment. Therapeutic approaches that intervene in the brain's signal transmission to keep brain tissue alive as much as possible after a stroke are not yet possible.
The research group led by Univ.-Prof. Dr. Johannes Vogt (Cologne), Univ.-Prof. Dr. Frauke Zipp (Mainz) and Univ.-Prof. Dr. Dr. Robert Nitsch (Münster), has now shown that the control of the excitability of neurons by lysophosphate acid (LPA) has a major impact on the course of stroke: Increased synaptic lipid signals amplify glutamate-triggered stimulus flooding. The molecule autotaxin (ATX) plays a central role in this process.
After an experimental stroke, a long-lasting increase of ATX concentrations and of the excitation-stimulating LPA in the brain could be demonstrated. Prof. Vogt explains, "We have been able to show via gene mutation and pharmacological inhibition of ATX, even hours after an experimental stroke, that tissue excitability controlled via LPA can be inhibited, thus significantly improving the course of the stroke."
Prof. Zipp, a neurologist from Mainz, associates the findings with an important clinical perspective: "Since both ATX and LPA concentrations in the cerebrospinal fluid (CSF) are elevated in those affected after the stroke, new therapeutic options are emerging that could have an impact even after the stroke itself."
Prof. Nitsch sees an important translational step for new drug development, "Indeed, the data show that patients with a disrupted synaptic LPA signaling pathway are more affected by stroke. This is a strong indication of potential therapeutic success with ATX inhibitors, which we are currently developing in collaboration with the Hans Knöll Institute in Jena."
The new findings on the hyperexcitability of neuronal networks and a new possibility for their therapeutic correction could be relevant in the future not only for stroke, but also for other neurological and psychiatric diseases.
Stroke is the leading cause of disability worldwide and the second leading cause of death. In Germany, about 270,000 people suffer a stroke every year. The majority of cases involve ischemia, which is the blockage of an artery in the brain that causes a circulatory disturbance.
Modified press release by Uniklinik Köln
Original Publication
Lynn Bitar*, Timo Uphaus*, Carine Thalman*, Muthuraman Muthuraman, Luzia Gyr, Haichao Ji, Micaela Domingues, Heiko Endle, Sergiu Groppa, Falk Steffen, Nabin Koirala, Wei Fan, Laura Ibanez, Laura Heitsch, Carlos Cruchaga, Jin-Moo Lee, Florian Kloss, Stefan Bittner, Robert Nitsch#, Frauke Zipp#, Johannes Vogt#. Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke. Science Translational Medicine, 20 April 2022, Vol 14, Issue 641.DOI: 10.1126/scitranslmed.abk0135