Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic–ischemic brain injury

Morán, Javier; Stokowska, Anna; Walker, Frederik R.; Mallard, Carina; Hagberg, Henrik; Pekna, Marcela

doi:10.1016/j.expneurol.2017.01.001

Cited by 35 publications

(33 citation statements)

References 59 publications

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“…Therefore, efforts to reduce neuronal loss in combination with enhancing poststroke neural remodeling and neural plasticity provide a promising means to potentiate functional recovery. Strategies aimed at blunting the inflammatory response after stroke by depleting microglia or astrocytes have shown increased injury due to the beneficial homeostatic roles of these cells (Li et al, 2008;Szalay et al, 2016). Compared with other strategies, a unique advantage of acutely inhibiting complement amplification is that pathologic microglial and astrocyte activation is interrupted without affecting subsequent homeostatic activity required for recovery.…”

Section: Discussionmentioning

confidence: 99%

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Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

et al. 2018

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Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke. Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.

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Section: Discussionmentioning

confidence: 99%

“…Genes were considered differentially regulated for p Ͻ 0.01 on Student's t test performed on replicate data (n ϭ 5) as described previously (Geiss et al, 2008). Clustergrams and PCA were performed in MATLAB 2013 and analysis of gene ontology (GO) biological processes was performed using PANTHER (Mi et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

et al. 2018

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“…1d–f. This intranasal approach has been successfully used to deliver exogenous C3a to the mouse brain in previous studies [25, 26]. …”

Section: Methodsmentioning

confidence: 99%

Complement activation contributes to perioperative neurocognitive disorders in mice

Xiong

Lü

Lin

et al. 2018

J Neuroinflammation

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BackgroundThe complement system plays an important role in many neurological disorders.Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND.MethodsA stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker.ResultsC3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function.ConclusionsOrthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1292-4) contains supplementary material, which is available to authorized users.

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“…The most commonly used neonatal asphyxia model has been established in rodents by Rice-Vannucci in 1981 with unilateral common carotid artery (CCA) occlusion followed by systemic hypoxia (HI) leading to excitotoxicity, apoptosis, inflammation and subacute white and grey matter injury resulting in long-term brain atrophy mainly affecting cortex, hippocampus and striatum [66][67][68] . This type of injury leads to long-term sensorimotor deficits while general locomotor activity is only transiently increased resolving at 3 weeks of age 67,69,70 . This transient increase in locomotor activity may reflect hyperactivity, a major hallmark of ADHD.…”

Section: Hypoxia-ischaemia (Hi)mentioning

confidence: 99%

Adverse neuropsychiatric development following perinatal brain injury: from a preclinical perspective

et al. 2018

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Perinatal brain injury is a leading cause of death and disability in young children. Recent advances in obstetrics, reproductive medicine and neonatal intensive care have resulted in significantly higher survival rates of preterm or sick born neonates, at the price of increased prevalence of neurological, behavioural and psychiatric problems in later life. Therefore, the current focus of experimental research shifts from immediate injury processes to the consequences for brain function in later life. The aetiology of perinatal brain injury is multi-factorial involving maternal and also labour-associated factors, including not only placental insufficiency and hypoxia-ischaemia but also exposure to high oxygen concentrations, maternal infection yielding excess inflammation, genetic factors and stress as important players, all of them associated with adverse long-term neurological outcome. Several animal models addressing these noxious stimuli have been established in the past to unravel the underlying molecular and cellular mechanisms of altered brain development. In spite of substantial efforts to investigate short-term consequences, preclinical evaluation of the long-term sequelae for the development of cognitive and neuropsychiatric disorders have rarely been addressed. This review will summarise and discuss not only current evidence but also requirements for experimental research providing a causal link between insults to the developing brain and long-lasting neurodevelopmental disorders.

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Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic–ischemic brain injury

Cited by 35 publications

References 59 publications

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection

Complement activation contributes to perioperative neurocognitive disorders in mice

Adverse neuropsychiatric development following perinatal brain injury: from a preclinical perspective

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