Table 2.

Therapeutic potential of DNase/RNase treatment in preclinical animal models of neurological diseases

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]

ANG: angiogenin; ALS: amyotrophic lateral sclerosis; BBB: blood–brain barrier; cGAS: cyclic GMP-AMP synthase; CNS: central nervous system; ICH: intracerebral hemorrhage; icv: intracerebroventricular; IFN: interferon; ip: intraperitoneal; IS: ischemic stroke; iv: intravenous; MCAO: middle cerebral artery occlusion; n.d.: not determined; NET: neutrophil extracellular trap; PAI-1: plasminogen activator inhibitor 1; PND: postnatal day; POCD: postoperative cognitive dysfunction; RP: reperfusion; SAH: subarachnoid haemorrhage; sc: subcutaneous; STING: stimulator of interferon genes; tPA: tissue plasminogen activator; TBI: traumatic brain injury; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor