Infarct reduction in rats following intraventricular administration of either tissue plasminogen activator (tPA) or its non-protease mutant S478A-tPA

Yi, Jung-Sun; Kim, Yang‐Hee; Koh, Jae‐Young

doi:10.1016/j.expneurol.2004.05.032

Cited by 16 publications

(14 citation statements)

References 34 publications

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“…The brain-protective effect of TPA was only found in icv-injection rather than intravenous injection (data not shown). This was consistent with a previous study (14), perhaps because the receptor of TPA/Kringle-2 was located in parenchyma. Unlike plasmin and angiostatin, a number of lysine-binding Kringles, did not have the same brain-protective effect as TPA.…”

Section: Discussionsupporting

confidence: 82%

“…Interestingly, the protease domain of TPA actually has an adverse effect and causes brain damage. A non-proteolytic TPA mutant (S478A) was previously found also to reduce infarction in ischemic stroke (14).…”

Section: Discussionmentioning

confidence: 99%

“…Secondarily, at 15 min after MCAO, five groups of rats were icv-injected with 40 pmol of alteplase, reteplase, Kringle-2, P, plasmin and PBS, respectively. All rats were observed for total 24 h, in which they were ischemic for the first 2 h and then immediately reperfused for the remaining 22 h. At 24 h, the survival rates were evaluated and the infarct volumes were measured with 2,3,5-triphenyltetrazolium chloride staining (14).…”

Section: Methodsmentioning

confidence: 99%

“…However, brain protective effects of TPA have also been reported (13)(14)(15)(16)(17). An intracerebroventricular (icv) injection of TPA within 15 min after cerebral ischemia in rats has brainprotective effects independent of its plasminogen activator property (13)(14)(15). TPA attenuates zinc-induced cell death through the non-proteolytic function (15,16).…”

Section: Introductionmentioning

confidence: 99%

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The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats

Zhang

Bi²,

Xiao³

et al. 2010

Int J Mol Med

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Abstract. Tissue plasminogen activator (TPA) showed brainprotective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats

Zhang

Bi²,

Xiao³

et al. 2010

Int J Mol Med

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show abstract

“…100 It has also been noted that low-molecular-weight contaminants (potentially L-arginine) in commercial preparations of human rt-PA (alteplase) could cause cell toxicity, and similarly contaminants in plasmin preparations could stimulate neuron Ca +2 flux. u-PA, SK, and occasionally t-PA occlusion model in the Sprague-Dawley rat occurred when rt-PA (alteplase), the S478A mutant of t-PA, or denatured rt-PA were given by intracerebroventricular injection compared to control.…”

Section: Clinical Consequences Of Therapeutic Plasminogen Activationmentioning

confidence: 99%

Mechanisms of Thrombosis and Thrombolysis

Zoppo¹

2016

Stroke

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tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice

Uekawa,

Anfray,

Ahn

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONAmyloid beta (Aβ) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aβ accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aβ‐induced neurovascular and cognitive dysfunction.METHODSTg2576 mice and wild‐type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later.RESULTSTreatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid.DISCUSSIONThese findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution.Highlights Amyloid beta (Aβ) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aβ. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aβ and tPA reconstitution may be of therapeutic value.

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Infarct reduction in rats following intraventricular administration of either tissue plasminogen activator (tPA) or its non-protease mutant S478A-tPA

Cited by 16 publications

References 34 publications

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats

Mechanisms of Thrombosis and Thrombolysis

tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice

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