Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Paine, Michael G.; Che, Dongsheng; Li, Luchuan; Neumar, Robert W.

doi:10.1016/j.resuscitation.2012.05.022

Cited by 22 publications

(12 citation statements)

References 40 publications

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“…Rodent models of cerebral ischemia have been used extensively to examine injury mechanisms and neuroprotective therapies in cortex, striatum and hippocampus (Merchenthaler et al ., 2003; Traystman, 2003; Kofler et al ., 2004; Noppens et al ., 2008). However, fewer studies have focused on the cerebellum following global ischemia, despite data indicating that cerebellar Purkinje cells are highly vulnerable to cerebral ischemia (Ng et al ., 1989; Horn & Schlote, 1992; Welsh et al ., 2002; Paine et al ., 2012). Movement disorders are often observed in cardiac arrest survivors and are attributed primarily to striatal damage, but it is likely that cerebellar injury also contributes to motor deficits in post-cardiac arrest patients (Venkatesan & Frucht, 2006; Lu-Emerson & Khot, 2010).…”

Section: Introductionmentioning

confidence: 99%

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Quillinan¹,

Grewal²,

Deng³

et al. 2015

Neuroscience

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Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. NMDA receptor mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicates that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 hours after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on Purkinje cell loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.

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Section: Introductionmentioning

confidence: 99%

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Quillinan¹,

Grewal²,

Deng³

et al. 2015

Neuroscience

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“…Purkinje neurons are vulnerable to global ischemia after asphyxial cardiac arrest in both developing [22] and adult rats [21]. Purkinje neurons were distinguished using calbindin immunohistochemistry.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to being prone to neurodegeneration via dysregulation of autophagy [2], cerebellar Purkinje cells are exquisitely vulnerable to HI [20,21], both perhaps related to the fact that Purkinje cells have one of the highest metabolic rates of any class of neurons. Purkinje cell vulnerability to HI and proclivity toward autophagy-induced neurodegeneration, in combination with the cerebellum's proximity to the intracisternal space, provided us with the opportunity to directly evaluate the role of autophagy after global brain HI in vivo , using a siRNA strategy.…”

Section: Introductionmentioning

confidence: 99%

Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro

Chen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16–18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation. Two days before a 9 min asphyxial cardiac arrest or sham surgery, Atg7 or control siRNA was injected intracisternally to target the cerebellum. Treatment with Atg7 siRNA: 1) reduced Atg7 protein expression in the cerebellum by 56%; 2) prevented the typical ischemia-induced formation of LC3-II in the cerebellum 24 h after asphyxial cardiac arrest; 3) improved performance on the beam-balance apparatus on days 1–5; and 4) increased calbindin-labeled Purkinje cell survival assessed on day 14. Improved Purkinje cell survival was more consistent in female vs. male rats, and improved beam-balance performance was only seen in female rats. Similar responses to Atg7 siRNA i.e. reduced autophagy and neurodegeneration vs. control siRNA were seen when exposing sex-segregated green fluorescent protein-LC3 tagged mouse primary cortical neurons to oxygen glucose deprivation in vitro. Thus, inhibition of autophagy after global ischemia in PND 16–18 rats leads to increased survival of Purkinje cells and improved motor performance in a sex-dependent manner.

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“…The conclusion of this research was that hypothermia exerts its greatest neuroprotective benefit 8 to 24 hours post-cardiac arrest. 8 The AHA recommends therapeutic hypothermia be maintained between 32 C and 34 C for at least 12 and up to 24 hours. 2,6 Ventilation Research has shown hyperventilation increases neurodegeneration.…”

Section: Maintaining Target Temperaturementioning

confidence: 99%

Therapeutic Hypothermia After Cardiac Arrest and Return of Spontaneous Circulation

Beseda

Smith

Veenstra

2014

Critical Care Nursing Clinics of North America

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Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Cited by 22 publications

References 40 publications

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro

Therapeutic Hypothermia After Cardiac Arrest and Return of Spontaneous Circulation

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