Strong neuroprotection with a novel platinum nanoparticle against ischemic stroke- and tissue plasminogen activator-related brain damages in mice

Abstract

Reactive oxygen species (ROS) are major exacerbation factor in acute ischemic stroke, and thrombolytic agent tissue plasminogen activator (tPA) may worsen motor function and cerebral infarcts. The platinum nanoparticle (nPt) is a novel ROS scavenger, and thus we examined the clinical and neuroprotective effects of nPt in ischemic mouse brains. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min and divided into the following four groups by intravenous administration upon reperfusion, vehicle, tPA, tPA+nPt, and nPt. At 48 h after tMCAO, motor function, infarct volume, immunohistochemical analyses of neurovascular unit (NVU), in vivo imaging of matrix metalloproteinase (MMP), and zymography for MMP-9 activity were examined. Superoxide anion generation at 2h after tMCAO was also examined with hydroethidine (HEt). As a result, administration of tPA deteriorated the motor function and infarct volume as compared to vehicle. In vivo optical imaging of MMP showed strong fluorescent signals in affected regions of tMCAO groups. Immunohistochemical analyses revealed that tMCAO resulted in a minimal decrease of NAGO and occludin, but a great decrease of collagen IV and a remarkable increase of MMP-9. HEt stain showed increased ROS generation by tMCAO. All these results became pronounced with tPA administration, and were greatly reduced by nPt. The present study demonstrates that nPt treatment ameliorates neurological function and brain damage in acute cerebral infarction with neuroprotective effect on NVU and inactivation of MMP-9. The strong reduction of ROS production by nPt could account for these remarkable neurological and neuroprotective effects against ischemic stroke.

Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation/mobilization of progenitor cells in infarcted rat brain

“…We have previously shown that delivery of SOD-loaded NPs via carotid artery at the time of reperfusion in an MCAO model in rats was significantly more effective in preventing reperfusion injury than SOD in solution or untreated control; treatment with antioxidant NPs mitigated the ROS levels, reduced BBB leakage, and protected neuronal cells from apoptosis, leading to steady neurological recovery with concomitant reduction in infarct volume over 4 weeks [17]. Others have also demonstrated similar efficacy in the MCAO model with antioxidant-loaded NPs [38] and other formulations of NPs that mitigated the ROS levels in the ischemic brain [39]. …”

Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation

“…Moreover, rtPA treatment initiated after the therapeutic window may even worsen ischemic brain injury. rtPA-induced brain damage has been found to be associated with increased ROS (Takamiya et al, 2012), so coadministration of rtPA with agents that dampen ROS production might afford robust cerebroprotection. However, conventional antioxidants have been found generally ineffective at protecting ischemic brain or preserving neurocognitive function in stroke victims (Sutherland et al, 2012).…”

Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

“…173 Similarly, platinum nanoparticles showed their antioxidant property which reported lowering cerebral cortex volume and improved motor function in stroke animal model. 174 Irreversible caspase-3 inhibitor loaded transferrin targeted nanospheres provide a reduction in infarct volume in ischemic brain. 175 SiRNA loaded carbon nanotube also documented as potential therapeutics in stroke treatment.…”