Progranulin Deficiency Promotes Post-Ischemic Blood–Brain Barrier Disruption

Jackman, Katherine; Kahles, Timo; Lane, Diane; García-Bonilla, Lidia; Abe, Takato; Capone, Carmen; Hochrainer, Karin; Voss, Henning U.; Zhou, Ping; Ding, Aihao; Anrather, Josef; Iadecola, Costantino

doi:10.1523/jneurosci.4318-13.2013

Cited by 85 publications

(80 citation statements)

References 64 publications

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“…First, we cannot exclude the possibility that anti-inflammation may play a role in the neuroprotective effect of PGRN (13, 14). In addition, it has recently been reported that PGRN deficiency leads to major alterations in blood-brain barrier (BBB) structure and function that predispose PGRN-knockout mice to BBB breakdown and increased ischemic brain injury, implying that PGRN also has an important vasoprotective effect (25). Thus, the link between different protective effects of PGRN needs to be considered in future studies.…”

Section: Discussionmentioning

confidence: 99%

Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats

et al. 2015

Critical Care Medicine

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Objectives Progranulin has been reported to have neuroprotective actions in cultured neurons. This study investigated the effect of recombinant rat progranulin on early brain injury after subarachnoid hemorrhage. Design Controlled in vivo laboratory study. Setting Animal research laboratory. Subjects Two hundred thirty adult male Sprague-Dawley rats weighing 280–320 g. Interventions Subarachnoid hemorrhage was induced in rats by endovascular perforation. Rat recombinant progranulin (1 and 3 ng) was administrated intracerebroventricularly at 1.5 hours after subarachnoid hemorrhage. Progranulin small interfering RNA was administrated by intracerebroventricularly at 1 day before subarachnoid hemorrhage induction. Subarachnoid hemorrhage grade, neurologic score, and brain water content were measured at 24 and 72 hours after subarachnoid hemorrhage. Neural apoptosis was evaluated by double immunofluorescence staining using terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick-end labeling and neuronal nuclei. For mechanistic study, the expression of progranulin, phosphorylated Akt, Akt, p-Erk, Erk, Bcl-2, and cleaved caspase-3 were analyzed by Western blot at 24 hours after subarachnoid hemorrhage. siRNA for sortilin 1 (a progranulin receptor) was used to intervene the downstream pathway. Measurements and Main Results The expression of progranulin decreased and reached the lowest point at 24 hours after subarachnoid hemorrhage. Administration of rat recombinant progranulin decreased brain water content and improved neurologic functions at both 24 and 72 hours after subarachnoid hemorrhage, while knockdown of endogenous progranulin aggravated neurologic deficits after subarachnoid hemorrhage. Rat recombinant progranulin treatment reduced neuronal apoptosis, while progranulin deficiency promoted neuronal apoptosis at 24 hours after subarachnoid hemorrhage. Rat recombinant progranulin promoted Akt activation, increased Bcl-2 level, but reduced caspase-3 level. Knockdown of progranulin binding factor sortilin 1 abolished the beneficial effects of rat recombinant progranulin at 24 hours after subarachnoid hemorrhage. Conclusion Rat recombinant progranulin alleviated neuronal death via sortilin 1-mediated and Akt-related antiapoptosis pathway. Rat recombinant progranulin may have potentials to ameliorate early brain injury for subarachnoid hemorrhage patients.

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Section: Discussionmentioning

confidence: 99%

Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats

et al. 2015

Critical Care Medicine

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“…The early phase begins after reperfusion, reaches its peak approximately 6 h after the onset of cerebral ischemia, and recovers, mostly or completely, in the successive 8–24 h [1, 8–11]. This early phase is caused primarily by an increase in endothelial transcytosis, characterized by little or no degradation of tight junction [10, 12], and resulting in a marked cerebral extravasation of plasma albumin and related intravascular tracers [1, 8–14] such as the Evans blue dye (EBD) [1, 8, 9, 11, 13, 14]. Interestingly, the augmented transcytosis that occurs in the early phase of BBB disruption does not result in a noticeable increase in extravasation of small molecules or immunoglobulins [10].…”

Section: Introductionmentioning

confidence: 99%

“…Because early-phase BBB disruption is characterized by the selective leakage of albumin but not of other intravascular tracers [10], BBB permeability was quantified by measuring the cerebral extravasation of the albumin-binding tracer EBD. In fact, with a cerebral extravasation property that is distinct from that of a non-albumin-binding tracer [18], EBD is able to extravasate in the early phase of BBB disruption [1, 8, 9, 11, 13]. …”

Section: Introductionmentioning

confidence: 99%

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia

et al. 2017

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Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8–24 h, whereas the late phase of BBB disruption begins 48–58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.

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“…BBB dysfunction during cerebral ischemia was also associated with increased phosphorylation of PDGFR-α and provided the mechanistic outline for a tPA – PDGF-CC – PDGFR-α signaling axis in vivo . The effect of BBB disruption after intracerebral injection of PDGF-CC was confirmed in another study (Jackman et al, 2013), which showed that genetic deficiency for progranulin ( Pgrn ) exacerbates the degree of PDGF-CC – induced BBB dysfunction. Together, these findings provide a novel concept to pharmacologically target the PDGF-CC pathway to prevent or reduce BBB dysfunction in a range of neurological disorders.…”

Section: Tpa – Pdgf-cc – Pdgfr-α Signaling Axis In the Cns: Means mentioning

confidence: 79%

Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

Lewandowski

Fredriksson

Lawrence

et al. 2016

Pharmacology & Therapeutics

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Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis. Stroke and traumatic injuries are major risk factors for age-associated neurodegenerative disorders and we speculate that restoring BBB properties through PDGF-CC inhibition might provide a common therapeutic opportunity for treatment of both acute and progressive neuropathology in humans. In this review we will summarize what is known about the role of PDGF-CC in neurovascular signaling events and the variety of seemingly different neuropathologies it is involved in. We will also discuss the pharmacological means of therapeutic interventions for anti-PDGF-CC therapy and ongoing clinical trials. In summary: inhibition of PDGF-CC signaling can be protective for immediate injury and decrease the long-term neurodegenerative consequences.

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Progranulin Deficiency Promotes Post-Ischemic Blood–Brain Barrier Disruption

Cited by 85 publications

References 64 publications

Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats

Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia

Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

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