Introduction: Cerebral vasospasm (CV) and related ischemic injury is a major contributor to death and disability after aneurysmal subarachnoid hemorrhage (aSAH). Mechano-growth-factor (MGF) - a splice variant of insulin-like growth factor 1 (IGF-1) - has been shown to exhibit neuroprotective effects. Our goal is to understand the molecular mechanisms underlying CV and the role of MGF in the development of CV to facilitate the development of safe and effective diagnostic and treatment paradigms for CV. Our hypothesis is that specific early changes in microparticle-derived MGF mRNA and protein expression attenuate CV development and prevent it from having its damaging effects.
Methods: Cerebro-spinal fluid (CSF) was collected daily from patients with aSAH. Microparticles (MP) were isolated using serial ultracentrifugation. Differential mRNA and protein expression of MGF and related molecules in CSF-MPs were analyzed using quantitative real time RT-PCR (qRT-PCR), ELISA and Western Blot. These mRNA and protein levels were correlated with clinical data and used to identify candidates for pathological and/or neuroprotective pathways activated in development and progression of CV.
Results: Daily CSF-derived MGF, IGF-1 and heme-oxygenase-1 (HO-1) mRNAs were analyzed. Increased expression of these genes showed a correlation with the onset of CV. The same was true when MGF protein expression was analyzed. There was a simultaneous increase in MGF and HO-1 mRNA levels in the CSF of CV patients indicating that MGF may exert its neuroprotective role via HO-1 pathway.
Conclusions: This is the first demonstration of differential MGF expression in CSF-MPs from CV patients and correlation of an increase in MGF mRNA with increased HO-1 mRNA. These data indicate that MGF may act through HO-1 pathway to exert its neuroprotective effects and that this pathway is associated with progression of CV. Further studies need to be performed in order to further confirm this hypothesis in aSAH patients.
Patient Care: Our research will contribute to a better understanding of the etiology associated with the development of CV after aSAH and potentially lead to the development of effective treatment strategies for aSAH related CV.
Learning Objectives: To understand the role of MGF in the development of CV post aSAH.