RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis

Abstract

The sole Food and Drug Administration-approved treatment for acute stroke is tissue-type plasminogen activator (tPA), but tPA aggravates impairment of cerebrovasodilation during hypotension in a newborn pig photothrombotic model of stroke. Coupling to carrier red blood cells (RBC) enhances thrombolytic effects of tPA, while reducing its side effects. ATP- and Ca-sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate cerebrovasodilation during hypotension. Mitogen-activated protein kinase, a family of at least three kinases, ERK, p38, and c-Jun-N-terminal kinase (JNK), is upregulated after photothrombosis. This study examined the effect of photothrombosis on Katp- and Kca-induced cerebrovasodilation and the roles of tPA and JNK during/after injury. Photothrombosis blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene-related peptide, and the Kca agonist NS 1619, which was aggravated by injection of tPA. In contrast, both pre- or post-injury thrombosis injection of RBC-tPA and JNK antagonist SP 600125 prevented impairment of Katp- and Kca-induced vasodilation. Therefore, JNK activation in thrombosis impairs K channel-mediated cerebrovasodilation. Standard thrombolytic therapy of central nervous system ischemic disorders using free tPA poses the danger of further dysregulation of cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone, whereas RBC-coupled tPA both restores reperfusion and normalizes cerebral hemodynamics.

Evolutional Characterization of Photochemically Induced Stroke in Rats: a Multimodality Imaging and Molecular Biological Study

“…Further, the consistent lesion made in the cortex where cellular changes evolve and follow a similar trend to those of the occlusive models makes it a suitable model for the study of neurorestorative therapy of pharmaceuticals or stem cells. In the scope of translational purpose, this method had been applied on animals other than rodents, such as rabbits and pigs [ 43 – 46 ].…”

Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude

“…As previously described 43 , 2–7-day-old Yorkshire pigs were anesthetized, endotracheally intubated, cannulated in the left internal jugular (for NC injection) and right femoral artery (for blood pressure and blood gas monitoring) and then injected IV with NCs, followed by radiotracer biodistribution measurement as for the mice.…”

Red Blood Cell Hitchhiking: A Novel Approach for Vascular Delivery of Nanocarriers

“…These methods for RBC surface loading have been successfully employed to attach to RBC antithrombotic and anti-inflammatory recombinant proteins, antigens for modulation of the immune response, and glycoproteins protecting RBCs from complement (65)(66)(67)(68)(69). Therapeutic targets of these agents are accessible for RBC-drug complexes circulating in the bloodstream.…”