Immunohistochemical expression of Bcl-2, Bax and cytochrome c following focal cerebral ischemia and effect of hypothermia in rat

Babu, Phanithi Prakasa; Yoshida, Yasuji; Su, Mu; Segura, Miguel F.; Kawamura, Shingo; Yasui, Nobuyuki

doi:10.1016/s0304-3940(00)01404-x

Cited by 76 publications

(15 citation statements)

References 20 publications

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“…Consistent with these observations, hypothermia has been shown to inhibit activation of the inflammatory transcription factor nuclear factor kappa B (NFkB) via temperature-dependent inhibition of its inhibitor protein's kinase, IKK 23. Other studies indicate that hypothermia has antiapoptotic effects such as reduction of cytochrome C release, and inhibition of caspases and proapoptotic genes 25-29. Interestingly, although hypothermia downregulates a majority of cell death pathways, it also seems to upregulate cell survival pathways such as Akt16 or ERK22,30 and increase trophic factor secretion 17-20…”

Section: Therapeutic Hypothermiamentioning

confidence: 90%

Metabolic Downregulation

Yenari

Kitagawa

Lyden

et al. 2008

Stroke

141

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Background and Purpose-The search for effective neuroprotectants remains frustrating, particularly with regard to specific pharmaceuticals. However, laboratory studies have consistently shown remarkable neuroprotection with 2 nonpharmacological strategies-therapeutic hypothermia and ischemic preconditioning. Recent studies have shown that the mechanism of protection underlying both of these treatments is correlated to downregulation of cellular and tissue metabolism. Thus, understanding the mechanisms underlying such robust protective effects could lead to appropriate translation at the clinical level. In fact, hypothermia is already being used at many centers to improve neurological outcome from cardiac arrest. Methods-A systematic review of both topics is presented in terms of underlying pathophysiological mechanisms and application at the clinical level. Results-Although the mechanisms of protection for both therapeutic strategies are multifold, both share features of downregulating metabolism. Both therapeutic strategies are robust neuroprotectants, but translating them to the clinical arena is challenging, though not impossible, and clinical studies have shown or suggest benefits of both treatments. Conclusions-The strategy of metabolic downregulation should be further explored to identify effective neuroprotectants that can be easily applied clinically.

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Section: Therapeutic Hypothermiamentioning

confidence: 90%

Metabolic Downregulation

Yenari

Kitagawa

Lyden

et al. 2008

Stroke

141

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“…and attenuate cytochrome c release from mitochondria. 6,7 Hypothermia also prevents responses to ischemia that would otherwise promote apoptosis such as increased expression of p53 and attenuation of Akt activity. 8,9 Hypothermia is currently achieved through methods that force temperature below the internal homeostatic set point.…”

mentioning

confidence: 99%

Novel Thyroxine Derivatives, Thyronamine and 3-iodothyronamine, Induce Transient Hypothermia and Marked Neuroprotection Against Stroke Injury

Doyle

Suchland

Ciesielski

et al. 2007

Stroke

108

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Background and Purpose-Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T 1 AM) and thyronamine (T 0 AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T 1 AM-and T 0 AM-induced hypothermia protects against brain injury from experimental stroke. Methods-We tested T 1 AM and T 0 AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T 1 AM and T 0 AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented. Results-T 1 AM and T 0 AM administration reduced body temperature from 37°C to 31°C. Mice given T 1 AM or T 0 AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T 1 AM before ischemia displayed significantly smaller infarcts compared with controls. Pre-and postischemia treatments required the induction of hypothermia. T 1 AM and T 0 AM treatment in vitro failed to confer neuroprotection against ischemia. Conclusions-T 1 AM and T 0 AM, are potent neuroprotectants in acute stroke and T 1 AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T 1 AM and T 0 AM may underlie neuroprotection. T 1 AM and T 0 AM offer promise as treatments for brain injury.

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“…It is well known that Bcl-2 prevents apoptosis by regulating the mPT and thereby blocking cytochrome c release into the cytosol. On the other hand, Bax is a pro-apoptotic member of the Bcl-2 protein family and can form a mitochondrial channel, which is permeable to cytochrome c. Moreover, ischemic cerebral injury can result in the activation of Bax and other members of the Bcl-2 family (Prakasa et al, 2000). Recent studies in rats and gerbils have revealed that dysregulation of Bcl-2 family proteins can exacerbate ischemic neuronal injury.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Dauricine after Transient Middle Cerebral Artery Occlusion in Rats: Involvement of Bcl-2 Family Proteins

et al. 2010

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Previous studies have shown that the bisbenzyl isoquinoline alkaloid dauricine can protect the brain against ischemic damage. We investigated here whether dauricine could inhibit neuronal apoptosis and modulate Bcl-2 family protein levels in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats underwent a 60 min temporary occlusion of the middle cerebral artery (MCAO). Two doses of dauricine (5 and 10 mg/kg as low and high dose respectively) were administered intraperitoneally at 1 hour after MCAO. After neurological deficits were assessed at 3 hours and 24 hours of reperfusion, rats were killed and brain samples were collected. Apoptotic changes were evaluated by TUNEL method. The immunohistochemistry and Western blot were used to assess the protein expressions of Bcl-2 and Bax. RT-PCR was used to determine Bcl-2 and Bax mRNA expressions. Dauricine (5 and 10 mg/kg) treatment improved neurological deficits, diminished DNA fragmentation, increased Bcl-2 expression and reduced Bax expression in the penumbra. The infarct-reducing effects of dauricine may be due, in part, to the inhibition of apoptotic cell death via modulation Bcl-2 family protein in the penumbra.

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Immunohistochemical expression of Bcl-2, Bax and cytochrome c following focal cerebral ischemia and effect of hypothermia in rat

Cited by 76 publications

References 20 publications

Metabolic Downregulation

Metabolic Downregulation

Novel Thyroxine Derivatives, Thyronamine and 3-iodothyronamine, Induce Transient Hypothermia and Marked Neuroprotection Against Stroke Injury

Neuroprotective Effect of Dauricine after Transient Middle Cerebral Artery Occlusion in Rats: Involvement of Bcl-2 Family Proteins

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