Mechanisms and Functional Significance of Stroke-Induced Neurogenesis

Marlier, Quentin; Verteneuil, Sébastien; Vandenbosch, Renaud; Malgrange, Brigitte

doi:10.3389/fnins.2015.00458

“…These activated microglia, in turn, release TNF-α, which induces neuron apoptosis in a caspase-3 dependent pathway [70]. There is a growing body of evidence that many neuronal subpopulations express TLRs, including TLR4 [132][133][134][135]. Mice with a defect in TLR4 are generally more resistant to CNS trauma [62], suggesting that TLR4 activation is detrimental to neuronal survival.…”

Section: Neuronsmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2016

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

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“…Recent studies showed that the brain possesses the ability to generate newly born cells from stem or neural progenitor cells in the subventricular zone and subgranular zone of the dentate gyrus. It was reported that division of these cells in the adult brain was enhanced by ischemic injuries, and newly produced cells became integrated in the neural network and participated in recovery [1][2][3] . In contrast to the adult brain, published data about endogenous regeneration in the developing rodent brain after ischemic injury are conflicting.…”

Section: Introductionmentioning

confidence: 99%

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain

Engels

¹

,

Elting²,

Braun³

et al. 2017

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Background: Hypoxic-ischemic (HI) injury to the developing brain occurs in 1 out of 1,000 live births and remains a major cause of significant morbidity and mortality. A large number of survivors suffer from long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after HI insult are not clearly understood, and preventive measures or clinical treatments are nonexistent or not sufficiently effective in the clinical setting. Sildenafil as a specific phosphodiesterase 5 inhibitor leads to increased levels of the second messenger cyclic guanosine monophosphate (cGMP) and promotes functional recovery and neurogenesis after ischemic injury to the adult brain. Objective: Here, we investigated the effect of sildenafil treatment on activation of intracellular signaling pathways, histological and neurogenic response including functional recovery after an ischemic insult to the developing brain. Design/Methods: Nine-day-old C57BL/6 mice were subjected either to sham operation or underwent ligation of the right common carotid artery followed by hypoxia (8%) for 60 min. Animals were either administered sildenafil (10 mg/kg, i.p.) or vehicle 2 h after hypoxia. A subgroup of animals received multiple injections of 10 mg/kg daily on 5 consecutive days. Pups were either perfusion fixed at postnatal days 14 or 47 for immunohistochemical analysis, or brains were dissected 2, 6, 12, and 24 h after the end of hypoxia and analyzed for cGMP, pAkt, pGSK-3β, and β-catenin by means of ELISA or immunoblotting. In addition, behavioral studies using the wire hang test and elevated plus maze were conducted 21 and 38 days after HI injury. Results: Based on cresyl violet staining, single or multiple sildenafil injections did not reveal any differences in injury scoring compared to sham animals. However, cerebral levels of cGMP were altered after sildenafil therapy. Treatment significantly increased numbers of immature neurons, as indicated by doublecortin immunoreactivity in the ipsilateral subventricular zone and striatum. In addition, animals treated with sildenafil after HI insult demonstrated improved functional recovery. pAkt, pGSK-3β, and β-catenin levels vary after HI injury but additional sildenafil treatment had no impact on protein expression compared to the level of sham controls. Conclusions: Here, we report that treatment with sildenafil after HI insult did not improve histological brain injury scores. Nevertheless, our results suggest involvement of the cGMP and PI3K/Akt/GSK-3β signaling pathway with promotion of a neurogenic response and reduction of neurological deficits. In summary, sildenafil may have a role in promoting recovery from HI injury in the developing brain.

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“…After acute ischemia, proliferation of these, and other, progenitor cells in the CNS is enhanced [88,136,137], and, similarly, shorter pulses of ischemia to induce preconditioning effects also result in the proliferation of progenitors [137,138], with an increase of up to 4-fold observed after preconditioning in one study [137]. Interestingly, when prolife r a t i o n w a s a t t e n u a t e d b y a d m i n i s t r a t i o n o f methylazoxymethanol acetate or ganciclovir, the preconditioning effect of a short ischemic event (15 min MCAO) was abolished [137].…”

Section: Progenitor Cellsmentioning

confidence: 99%

“…Adult neurogenesis occurs in well-characterized neurogenic niches, such as the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus, in both the normal adult brain and the ischemia-injured brain [136]. After acute ischemia, proliferation of these, and other, progenitor cells in the CNS is enhanced [88,136,137], and, similarly, shorter pulses of ischemia to induce preconditioning effects also result in the proliferation of progenitors [137,138], with an increase of up to 4-fold observed after preconditioning in one study [137].…”

Section: Progenitor Cellsmentioning

confidence: 99%

Correction to: Neuroimmune Response in Ischemic Preconditioning

McDonough

¹

,

Weinstein

²

2018

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Tolllike receptors and type 1 interferons. Brain ischemia results in release of pro-and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammatory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke. Keywords PreconditioningIschemic preconditioning (IPC) is an experimental phenomenon in which a brief period of ischemia confers robust neuroprotection against subsequent ischemic events [1-3]. It is important to note that preconditioning does not reduce the incidence of stroke, but rather ameliorates the pathophysiologic response to cerebral ischemia and results in a smaller infarct volume and improved poststroke recovery [4][5][6]. Clinical studies suggest that patients with stroke who suffered a recent prior transient ischemic attack have better outcomes than those who did not, implying that a human correlate to experimental IPC exists [7,8]. Elucidating the mechanisms of IPC is considered a critical challenge in stroke research [9,10]. Recent literature has implicated innate immune pathways, including Toll-like receptors (TLRs) [11,12] and type 1 interferon (IFN) signaling [5,11,13] in IPC-mediated protection.Due to a technical error in the production process, the earlier version of this article contained numerous errors in the reference numbering. We are reprinting the entire article in the correction for readabilityThe online version of the original article can be found at https://doi

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Mechanisms and Functional Significance of Stroke-Induced Neurogenesis

Cited by 65 publications

References 202 publications

Neuroimmune Response in Ischemic Preconditioning

Neuroimmune Response in Ischemic Preconditioning

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain

Correction to: Neuroimmune Response in Ischemic Preconditioning

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