Anti‐edematous effect of neurolysin in ischemic stroke
Authors: Nozohouri Saeideh , Jayaraman Srinidhi , Vaidya Bhuvan , Karamyan Vardan , Abbruscato Thomas 
Published: June 2021

During ischemic stroke brain injury occurs due to oxygen and nutrient deficiency, which initiates secondary injury cascades, including intracellular sodium and calcium accumulation, release of neurotoxic dopamine and glutamate, ion gradient dissipation, accumulation of reactive oxygen species, mitochondrial dysfunction, and excitotoxicity. All of these pathophysiologic processes contribute to cellular and vasogenic edema, which can be a life‐threatening effect of stroke and the primary reason for patient mortality after stroke.

Neuropeptides similar to neurotransmitters play a significant role in different signaling pathways. They act on the cellular surface after releasing into the extracellular spaces and their functions are terminated by endogenous neuropeptidases. Neurolysin (Nln), a zinc metallopeptidase, has been reported to be up‐regulated during stroke and plays a crucial role in the improvement of stroke outcomes. Functional importance of this enzyme in post‐stroke brain repair is due to its capability in processing a diverse group of neuropeptides, such as substance P, bradykinin and neurotensin, which all have distinct functions in the development of inflammation, excitotoxicity, and cell death after stroke. The objective of our present study was to investigate the role of Nln through the deactivation of the above neuropeptide substrates and subsequent reduction of brain edema after a model of ischemic stroke.

For an ex‐vivo model of ischemia, an acute brain slice model has been used. Briefly, 5–7 month old CD1 male mouse brain was extracted and 400 μm slices were exposed to 1 hour of oxygen glucose deprivation (OGD) condition followed by reperfusion (R) for 2 hours in the presence and absence of Nln substrates, i.e., substance P, bradykinin and neurotensin. To study the role of Nln, Nln substrates were co‐incubated with Nln during OGD/R. We observed that the 21% water content in slices increased when exposed to OGD/R compared to normoxia which further increased in the presence of Nln substrates during reperfusion, suggesting the role of Nln substrate in edema formation. Interestingly, the presence of rNln attenuated the enhanced edema formation by Nln substrates. These results indicated the role of Nln in reducing brain edema during ischemic stroke. Furthermore, to confirm that the effect of Nln is through deactivation of neuropeptides, we confirmed the hydrolysis of neuropeptides in the presence of Nln by using the LC‐MS/MS method.

These results imply that cellular edema formation after stroke can be worsened by common Nln substrates (substance P, bradykinin, and neurotensin), which all have well‐documented neurovascular effects that exacerbate brain edema formation, and treatment with rNln can significantly attenuate cerebral swelling. This study is instrumental in explaining the possible role of Nln substrates and their deleterious effect in edema formation during a stroke and further studies are needed to study the positive role of Nln activation in stroke recovery and reduction of brain edema.

Support or Funding Information

This research was supported by NIH R01 NS106879 to VK and TA.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.