The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity

Abstract

Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients.

Figure 1

Forest plot summarizing the data for the effect of recombinant tissue plasminogen activator (rtPA) administration on infarct volume in models of mechanical focal cerebral ischemia. Subgroups are divided on the basis of duration of ischemia. Numbers after study title reflect the dose of rtPA (mg/kg). Numbers and letters after the study title reflect the strain of mice used. CI, confidence interval.

Figure 2

Forest plot summarizing the data for the effect of recombinant tissue plasminogen activator (rtPA) administration on infarct volume in models of mechanical focal cerebral ischemia. Subgroups are divided on the basis of species and model of ischemia. Numbers after study title reflect the dose of rtPA (mg/kg). Numbers and letters after the study title reflect the strain of mice used. CI, confidence interval.

Figure 3

Forest plot summarizing the data for the effect of -arginine administration on infarct volume in models of mechanical focal cerebral ischemia. Subgroups are divided on the basis of timing of histological evaluation relative to the onset of ischemia. Single numbers after study title reflect the dose of -arginine (mg/kg), and in the Zhang et al (2004a) experiments, the first number is the duration of ischemia and the second number is the timing of administration of -arginine. Letters after the study title reflect the strain of rats or model used. CI, confidence interval; dist, distal middle cerebral artery occlusion; prox, proximal middle cerebral artery occlusion; SD, Sprague Dawley; SHR, spontaneously hypertensive rat.

Figure 4

Forest plot summarizing the data for the effect of -arginine administration on infarct volume in models of mechanical focal cerebral ischemia. Subgroups are divided on the basis of timing of administration of -arginine relative to the onset of ischemia. Single numbers after study title reflect the dose of -arginine (mg/kg), and in the Zhang et al (2004a) experiments, the first number is the duration of ischemia and the second number is the timing of administration of -arginine. Letters after the study title reflect the strain of rats or model used. CI, confidence interval; dist, distal middle cerebral artery occlusion; prox, proximal middle cerebral artery occlusion; SD, Sprague Dawley; SHR, spontaneously hypertensive rat.

Figure 5

Potential mechanisms by which recombinant tissue plasminogen activator (rtPA) confers neurotoxicity during ischemia and its interaction with -arginine via nNOS and iNOS. The rtPA cleaves the NR1 subunit of the NMDA receptor increasing the flux of Ca²⁺ into the cell. This increase in intracellular Ca²⁺ concentration can lead to cell damage and death. The NMDA receptors, through the scaffolding protein PSD-95, can interact with nNOS, metabolizing -arginine to NO, which can also lead to cell damage and death. The rtPA can also activate LRP, which can facilitate the action of rtPA on NMDA receptors previously described. The LRP can also activate the transcription factor NF-κB, which upregulates the expression of iNOS. The iNOS metabolizes -arginine to NO leading to cell damage and death. iNOS, inducible nitric oxide synthase; LRP, low-density lipoprotein receptor-related protein; NF-κB, nuclear factor κ light-chain enhancer of activated B cells; NMDA-R, N-methyl--aspartate receptor; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PSD-95, postsynaptic density-95.