L-Arginine Levels in Blood as a Marker of Nitric Oxide–Mediated Brain Damage in Acute Stroke: A Clinical and Experimental Study

Abstract

Summary:There are no useful markers in blood of nitric oxide (NO)-mediated brain damage. Because L-arginine (L-arg) is the only known substrate for NO generation, the authors investigated the plasma profile of L-arg after cerebral ischemia, and the relationship of L-arg concentrations in blood with stroke outcome and infarct volume in a clinical and experimental study. L-Arg levels were determined with high-performance liquid chromatography in blood and CSF samples obtained on admission, and in blood 48 hours after inclusion, in 268 patients admitted with a hemispheric ischemic stroke lasting 8.2 ± 5.9 hours. Infarct volume was measured by days 4 to 7 using computed tomography. Plasma L-arg profiles were analyzed in a separate group of 29 patients seen within 8 hours of onset (median, 4.5 hours) and in 24 male Fischer rats treated with subcutaneous vehicle or 20-mg/kg 1400W (a specific inducible NO synthase inhibitor) every 8 hours for 3 days after performing sham or permanent middle cerebral artery occlusion. Plasma L-arg concentrations decreased after the ischemic event, both in patients and rats, and peaked between 6 and 24 hours.In patients, there was a highly correlation between L-arg levels in CSF and plasma at 48 hours (r ‫ס‬ 0.85, P<0.001). CSF and plasma L-arg concentrations negatively correlated with infarct volume (r ‫ס‬ −0.40 and r ‫ס‬ −0.35, respectively, P<0.001), and were significantly lower in patients with early neurologic deterioration and in those with poor outcome (Barthel index <85) at 90 days (P<0.001). In rats, the administration of 1400W resulted in a 55% significant reduction of infarct volume measured 72 hours after permanent middle cerebral artery occlusion, an effect that correlated with the inhibition caused by 1400W on the ischemia-induced decrease of plasma L-arg concentrations at 6 to 24 hours after the onset of the ischemia. Taken together, these data indicate that determination of L-arg levels in blood might be useful to evaluate the neurotoxic effects of NO generation. These findings might be helpful to guide future neuroprotective strategies in patients with ischemic stroke.

Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways

“…The levels of arginine within DMEM (398µmol/L) are approximately five times greater than that found in normal human plasma (77.4+/−18.2µmol/L) and in HSV-infected tissue microenvironments (Armengou et al, 2003; Luneburg et al, 2011), providing relevance of these studies to minimal dosing levels required for inhibition of HSV. peg-ArgI was effective in controlling HSV-1 and -2 replication across a broad range of MOIs, completely abrogating infectious virus production at low MOIs and being superior to acyclovir treatment across all MOIs.…”

Cerebral Endothelial Function Determined by Cerebrovascular Reactivity to L-Arginine

“…The activity of the inducible iNOS peaks only after 2 days and stays active up to 7 days [37]. As a consequence the concentration of the serum L-arginine decreases after the ischemic event [38]. …”

High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke

“…1 Plasma levels of these molecules have been described as markers of neurologic worsening and greater infarct Supplemental data at www.neurology.org volume. [2][3][4] These effects are probably independent of the acute phase reaction or prior comorbidity, so levels of these molecules in blood might reflect the magnitude of their release in the ischemic brain. In this context, the relationship between these plasma markers and END might be attributed to a potential enlargement of cerebral infarction, although this hypothesis has not been demonstrated.…”