Improved thrombolytic effect with focused ultrasound and neuroprotective agent against acute carotid artery thrombosis in rat

Abstract

Combination therapy with focused ultrasound (FUS) and a neuroprotective agent, BNG-1, was examined in an acute carotid thrombotic occlusion model using LED irradiation in rat to improve the thrombolytic effect of rt-PA. Seven treatment groups included (A) intravenous bolus injection of 0.45 mg/kg rt-PA, (B) intravenous bolus injection of 0.9 mg/kg, (C) sonothrombolysis with FUS alone, (D) oral administration of 2 g/kg BNG-1 for 7 days alone, (E) A + D, (F) A + C, and (G) A + C + D. Four comparison groups were made including (H) 0.45 mg/kg rt-PA 20% bolus +80% IV fusion + FUS, (I) 0.9 mg/kg rt-PA with 10% bolus + 90% intravenous fusion, (J) B + C, (K) B + D. At 7 days after carotid occlusion, small-animal carotid ultrasound and 7 T MR angiography showed the recanalization rate of ≤50% stenosis was 50% in group B and 83% in group I, but 0% in groups A and C and 17% in group D. Combination therapy improved recanalization rate to 50–63% in groups E and F, to 67–83% in groups J and K, and to 100% in groups G and H. Our study demonstrated combination therapy with different remedies can be a feasible strategy to improve the thrombolytic effect of rt-PA.

Efficacy and safety of sonothrombolysis in patients with acute ischemic stroke: A systematic review and meta-analysis

“…The low acute recanalization rate with intravenous recombinant tPA highlights the need for further studies regarding the acceleration of intravenous thrombolysis [25]. Multiple in vitro and animal studies have demonstrated the efficacy of ultrasound in accelerating therapeutic fibrinolysis [26][27][28]. In the present meta-analysis, we assessed the data collected in five RCTs evaluating the clinical safety and efficacy of sonothrombolysis in patients with acute ischemic stroke.…”

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications

“…It has been reported that combining diagnostic ultrasound with microbubbles can accelerate the fibrinolysis induced by urokinase (54 kDa) [ 115 ] and recombinant tissue plasminogen activator (rtPA, 70 kDa) [ 116 ], supporting that acoustic cavitation is one mechanism for accelerating thrombolysis. Similarly, Lee et al showed in an in vivo model that low-dose rtPA combined with FUS can produce thrombolysis equivalent to that for full-dose rtPA without FUS [ 117 ]. Wang et al further developed a clot-targeted microbubble that induced a superior clot-lysis effect compared with the untargeted group using 800 kHz therapeutic ultrasound [ 118 ].…”

MRI‐Guided High‐Intensity Focused Ultrasound as an Emerging Therapy for Stroke: A Review

“…They also suggested that with the reduction in acoustic power and the use of transducers with precision focus, HIFU thrombolysis can be achieved successfully within the main arteries of human brain without causing any vascular damage and bleeding of the sonicated vessels. A recent preclinical study examined combination therapy of HIFU and a neuroprotective agent BNG‐1 in an acute carotid thrombotic occlusion model using light‐emitting diode (LED) irradiation in rat to improve the thrombolytic effect of rt‐PA …”

“…They also suggested that with the reduction in acoustic power and the use of transducers with precision focus, HIFU thrombolysis can be achieved successfully within the main arteries of human brain without causing any vascular damage and bleeding of the sonicated vessels. A recent preclinical study examined combination therapy of HIFU and a neuroprotective agent BNG-1 in an acute carotid thrombotic occlusion model using light-emitting diode (LED) irradiation in rat to improve the thrombolytic effect of rt-PA. 68 As apparent from numerous preclinical studies, HIFU sonothrombolysis has lately emerged as a favorable tPA-free option for the treatment of AIS. [60][61][62][63][64][65] HIFU causes microbubble oscillation which causes mechanical disruption of the blood clot improving flow restoration.…”