Table 2 Therapeutic potential of DNase/RNase treatment in preclinical animal models of neurological diseases
From: Brain alarm by self-extracellular nucleic acids: from neuroinflammation to neurodegeneration
Disease | Experimental model | Drugs | Time of delivery | Outcomes | Potential mechanisms | References |
|---|---|---|---|---|---|---|
IS | C57BL/6 mice Permanent MCAO/24 h survival | rhDNase1 50 µg/animal ip and 10 µg/animal iv | 10 min after MCAO | Infarct volume reduced Functional outcome improved | Degradation of NETs in brain parenchyma | [296] |
C57BL/6 mice 1 h MCAO/24 h RP | rhDNase1 2.5 mg/kg | Immediately before MCAO | Plasma NET levels reduced Brain infarct size decreased Neurological and motor function improved | Disruption of NETs | [80] | |
C57BL/6 mice 2 h MCAO/24 h RP | rhDNase1 50 µg/animal ip 10 µg/animal iv 50 µg/animal ip | 15 min before MCAO 5 min before RP 10 h after RP | Infarct volume reduced | Prevention of NETosis probably through regulating vWF and PAI-1 | [460] | |
C57BL/6 mice Photothrombotic MCAO/24 h survival | rhtPA 10 mg/kg iv rhDNase1 50 µg/animal ip and 10 µg/animal iv 50 µg/animal ip | 2 h after MCAO 15 min before tPA 13 h after MCAO | Reduced BBB breakdown, cerebral hemorrhage neurological deficits in tPA/DNase-treated mice compared to tPA-treated mice | Suppression of tPA-induced upregulation of cGAS-STING and type 1 IFN signaling by clearance of NETs | [397] | |
C57BL/6 mice Permanent MCAO/3 or 14 days survival | rhDNase1 50 µg/animal ip and 10 µg/animal iv 50 µg/animal ip | 24 h or 7 d after MCAO every 12 h until day 3 or day 14 | BBB breakdown reduced Neovascularization and vascular remodeling increased | Prevention of stroke-induced STING-mediated production of IFN-β by disruption of NETs | [184] | |
C57BL/6 mice Photothrombotic MCAO/24 h survival | rhDNase1 50 µg/animal ip and 10 µg/animal iv | 3 h after MCAO | Vessel recanalization improved Infarct volume reduced Functional outcome improved | Disruption of NETs | [297] | |
C57BL/6 mice 1 h MCAO/24 h RP | rhDNase1 50 µg/animal ip 10 µg/animal iv 50 µg/animal ip rhDNase1 50 µg/animal ip and 10 µg/animal iv 50 µg/animal ip | 15 min before MCAO 5 min before RP 11 h after RP 1 h after RP 13 h after RP | Infarct volume reduced Functional outcome improved Infarct volume reduced Functional outcome not altered | Degradation of extracellular chromatin | [70] | |
Wistar rats 90 min MCAO/24 h RP | RNase1 (bacterial) 13–3375 µg/kg iv | 10 min before MCAO | Infarct volume reduced Vasogenic edema decreased Motor impairment improved | n.d | [387] | |
Wistar rats 90 min MCAO/24 h RP | RNase1 (bacterial) 42 µg/kg iv | Immediately before MCAO | Infarct volume reduced BBB hyperpermeability and vasogenic edema decreased | Blockage of VEGF-mediated disintegration of interendothelial tight junctions | [110] | |
ICH | Sprague–Dawley rats 200 µl autologous arterial blood at 20 µl/min icv 7 days survival | rhtPA 20 µg/animal icv rhDNase1 2000 IU/animal icv | 1 h after hematoma placement | Reduced ventricular dilation, neurological impairment astrogliosis in tPA/DNase-treated mice compared to tPA-treated mice | Potentiation of tPA-induced fibrinolysis by degradation of clot-associated cell-free DNA | [419] |
Sprague–Dawley rats 100 µl autologous arterial blood at 10 µl/min icv 3 days survival | rhtPA 20 µg/animal icv rhDNase1 2000 IU/animal icv | 1 h after hematoma placement | Improved hematoma resolution, brain swelling and neurological deficits in tPA/DNase-treated mice compared to tPA-treated mice | Potentiation of tPA-induced fibrinolysis by disintegration of NETs | [361] | |
SAH | C57BL/6 mice Endovascular filament perforation model 1 day survival | rhDNase1 50 µg/animal ip and 10 µg/animal iv | 3 h after SAH | NETs in brain parenchyma decreased Brain swelling reduced Neurological dysfunction improved Neuroinflammatory response alleviated | Disruption of NETs | [444] |
C57BL/6 mice Endovascular filament perforation model 1, 7 or 14 days survival | RNase-A (bovine) 42 µg/kg iv 42 µg/kg iv | Perioperative every 3 days until day 7 or day 14 | Accumulation of NETs reduced | n.d | [119] | |
TBI | C57BL/6 mice Controlled cortical impact model 24 h survival | RNase-A (bovine) 20–180 µg/kg ip | 0.5 and 12 h after TBI | Lesion volume reduced BBB breakdown and vasogenic edema decreased Functional outcome not altered | n.d | [196] |
CD-1 mice Controlled cortical impact model 24 h or 2 months survival | rhDNase1 5 mg/kg iv | 1 h after TBI | Vasogenic edema reduced Cerebral perfusion improved Acute and chronic neurobehavioral outcomes improved | Degradation of circulating and CNS-infiltrated NETs | [376] | |
POCD | C57BL/6 mice Unilateral nephrectomy 1, 3 or 7 days survival | RNase-A (bovine) 500 µg/animal sc 200 µg/animal ip 500 µg/animal sc | 0.5 h prior to right before 1 h after nephrectomy | Cognitive impairment attenuated Inflammatory cytokine expression in serum and hippocampus reduced Apoptosis in hippocampus decreased | n.d | [45] |
ALS | SOD1G93A C57B6.Cg-Tg mice | rhANG (RNase5) 1 µg/animal ip | 3×/week from PND 90 until PND 115 | Reduced spinal cord motoneuron loss and vascular network regression, delayed motor dysfunction and improved survival of SOD1G93A mice | n.d | [60] |
SOD1G93A C57B6.Cg-Tg mice | rhRNase4 10 µg/animal ip | 1×/week from 11 weeks of age until death | Slowed weight loss and enhanced neuromuscular function of SOD1G93A mice | n.d | [216] |