Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Shinoda, Sachiko; Schindler, Clara K.; Meller, Robert; So, Norman K.; Araki, Toshimitsu; Yamamoto, Akira; Lan, Jing-Quan; Taki, Waro; Simon, Roger P.; Henshall, David C.

doi:10.1172/jci200419971

Cited by 89 publications

(56 citation statements)

References 51 publications

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“…6A-F). In contrast, and in accordance with our previous data (Araki et al, 2002;Shinoda et al, 2004a;Shinoda et al, 2004b), in sham treated control animals neither the contralateral hippocampus, nor any other brain region, was affected by the KA-induced seizures (Fig. 6A,D).…”

Section: Reduction Of Ka-induced Brain Injury By Adenosine-releasing supporting

confidence: 93%

“…One week after cell transplantation, animals received unilateral stereotaxic microinjection of kainic acid (KA) into the basolateral amygdala nucleus based on stereotactic coordinates relative to bregma: AP = -0.94 mm, L = -2.85 mm, V = -3.75 mm (Franklin and Paxinos, 1997) as described (Araki et al, 2002;Shinoda et al, 2004b).…”

Section: Seizure Modelmentioning

confidence: 99%

“…To assess the therapeutic potential of adenosine releasing hMSC brain implants we selected a paradigm of kainic acid (KA) induced brain injury (Araki et al, 2002;Shinoda et al, 2004b), which allowed us to assess both seizure suppression and neuroprotection by cell mediated adenosine release. Under standard immunosuppression (cyclosporine 12.5 mg/kg, i.p., daily) adult male C57BL/6 mice received intrahippocampal implants of 125,000 H239-hMSCs (n = 12 mice), scrambled control hMSCs (n = 6), or a respective sham treatment (n = 6).…”

Section: Reduction Of Ka-induced Seizures By Adenosine-releasing Hmscmentioning

confidence: 99%

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Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Ren

Lan

et al. 2007

Experimental Neurology

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Cell therapies based on focal delivery of the inhibitory neuromodulator adenosine were previously shown to provide potent seizure suppression in animal models of epilepsy. However, hitherto used therapeutic cells were derived from rodents and thus not suitable for clinical applications. Autologous patient-derived adenosine-releasing cell implants would constitute a major therapeutic advance to avoid both xenotransplantation and immunosuppression. Here we describe a novel approach based on lentiviral RNAi mediated downregulation of adenosine kinase (ADK), the major adenosineremoving enzyme, in human mesenchymal stem cells (hMSCs), which would be compatible with autologous cell grafting in patients. Following lentiviral transduction of hMSCs with anti-ADK miRNA expression cassettes we demonstrate up to 80% downregulation of ADK and a concentration of 8.5 ng adenosine per ml of medium after incubating 10 5 cells for 8 hours. hMSCs with a knockdown of ADK or cells expressing a scrambled control sequence were transplanted into hippocampi of mice 1 week prior to the intraamygdaloid injection of kainic acid (KA). While mice with control implants expressing a scrambled miRNA sequence or sham treated control animals were characterized by KAinduced status epilepticus and subsequent CA3 neuronal cell loss, animals with therapeutic ADK knockdown implants displayed a 35% reduction in seizure duration and 65% reduction in CA3 neuronal cell loss, when analyzed 24h after KA-injection. We conclude that lentiviral expression of anti-ADK miRNA constitutes a versatile tool to generate therapeutically effective adenosine releasing hMSCs, thus representing a model system to generate patient identical autologous adult stem cell grafts.

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Section: Reduction Of Ka-induced Brain Injury By Adenosine-releasing supporting

confidence: 93%

Section: Seizure Modelmentioning

confidence: 99%

Section: Reduction Of Ka-induced Seizures By Adenosine-releasing Hmscmentioning

confidence: 99%

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Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Ren

Lan

et al. 2007

Experimental Neurology

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“…Most importantly, spontaneous seizures in Adk-tg mice appear to be non-injurious, indicating that the increased susceptibility to neuronal cell death (Fig. 4) is related to the spread of injurious KA-induced acute type IV seizures (Shinoda et al, 2004;Henshall and Simon, 2005). Our findings further imply that tight regulation of adenosine levels by ADK is a necessity and that moderate overexpression of ADK in the absence of astrogliosis or epileptogenesis is sufficient to induce spontaneous seizures (i.e.…”

Section: Spontaneous Seizures In Adk-tg Micementioning

confidence: 53%

Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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Epilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a critical link between astrocyte and neuron dysfunction in epilepsy. Here we studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach including a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A 1 receptors. In wild type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosineremoving astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures all coincided in a spatio-temporally restricted manner. Importantly, these spontaneous seizures were mimicked in untreated transgenic mice overexpressing ADK in brain or those lacking A 1 receptors. Conversely, mice with reduced forebrain ADK did not develop astrogliosis or spontaneous seizures. Our studies define ADK as critical upstream regulator of A 1 receptor mediated modulation of neuronal excitability and support the ADK hypothesis of epileptogenesis implicating that upregulation of ADK during astrogliosis provides a critical link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

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“…The upregulation of Bim is JNK dependent in mice since it is blocked by SP600125 (Murphy et al, 2010), although FoxO1 or 3a may also be important (Murphy et al, 2010;Shinoda et al, 2004). Bim is also upregulated after pilocarpine-induced seizures (Yang et al, 2007), but Bim levels were reported to decline after seizures caused by intraventricular KA (Korhonen et al, 2003).…”

Section: Bim Activation and Knockout Phenotype In Status Epilepticusmentioning

confidence: 99%

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Engel

Plesnila

Prehn

et al. 2011

J Cereb Blood Flow Metab

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The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.

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Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Cited by 89 publications

References 51 publications

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Adenosine dysfunction in astrogliosis: cause for seizure generation?

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

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