Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion

Linnik, Matthew D.; Miller, Jerry A.; Sprinkle-Cavallo, Jean; Mason, Pamela; Thompson, Felisa Y.; Montgomery, Lauren R.; Schroeder, Kendra K.

doi:10.1016/0169-328x(95)00069-5

Cited by 150 publications

(57 citation statements)

References 32 publications

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“…In cerebral ischaemia, neurons at the core of the occlusion, where blood¯ow is severely reduced, are thought to die rapidly and mainly by necrosis, whereas neurons in the surrounding penumbra, where blood¯ow is less severely reduced, die by apoptosis (Dirnagl et al, 1999). Many investigators have localized apoptotic neurons to the border of the ischaemic lesion where energy depletion and excitotoxic stimulation are less severe and prolonged (Chopp et al, 1996;Du et al, 1996;Guegan et al, 1998;Linnik et al, 1995). The ability of AM-36 to inhibit apoptosis due to persistent Na + channel opening may contribute to the potent neuroprotection found in vivo in a rat model of cerebral ischaemia .…”

Section: A B C D E Fmentioning

confidence: 99%

“…Both Na + channel antagonists and free radical scavengers individually have been shown to reduce neuronal damage after cerebral ischaemia in experimental animals Rataud et al, 1994;Smith et al, 1996;Takamatsu et al, 1998;Umemura et al, 1994;Zhao et al, 1994). The importance of the role of free radicals is exempli®ed by the fact that even delayed treatment with antioxidants can be e ective in reducing neuronal damage of the ischaemic lesion and the ensuing neuronal death involve apoptotic mechanisms (Chopp et al, 1996;Du et al, 1996;Guegan et al, 1998;Linnik et al, 1995). ROS have been suggested to play a central role in the induction of apoptosis following exposure to a range of cytotoxic insults (Dirnagl et al, 1999;Jabs, 1999;Leist et al, 1998;Stoian et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Callaway¹,

Beart²,

Jarrott³

et al. 2001

British J Pharmacology

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1 AM-36 is a novel neuroprotective agent incorporating both antioxidant and Na + channel blocking actions. In cerebral ischaemia, loss of cellular ion homeostasis due to Na + channel activation, together with increased reactive oxygen species (ROS) production, are thought to contribute to neuronal death. Since neuronal death in the penumbra of the ischaemic lesion is suggested to occur by apoptosis, we investigated the ability of AM-36, antioxidants and Na + channel antagonists to inhibit toxicity induced by the neurotoxin, veratridine in cultured cerebellar granule cells (CGC's). 2 Veratridine (10 ± 300 mM) concentration-dependently reduced cell viability of cultured CGC's. Under the experimental conditions employed, cell death induced by veratridine (100 mM) possessed the characteristics of apoptosis as assessed by morphology, TUNEL staining and DNA laddering on agarose gels. 3 Neurotoxicity and apoptosis induced by veratridine (100 mM) were inhibited to a maximum of 50% by the antioxidants, U74500A (0.1 ± 10 mM) and U83836E (0.03 ± 10 mM), and to a maximum of 30% by the Na + channel blocker, dibucaine (0.1 ± 100 mM). In contrast, AM-36 (0.01 ± 10 mM) completely inhibited veratridine-induced toxicity ( IC 50 1.7 (1.5 ± 1.9) mM, 95% con®dence intervals (CI) in parentheses) and concentration-dependently inhibited apoptosis. 4 These ®ndings suggest veratridine-induced toxicity and apoptosis are partially mediated by generation of ROS. AM-36, which combines both Na + channel blocking and antioxidant activity, provided superior neuroprotection compared with agents possessing only one of these actions. This bifunctional pro®le of activity may underlie the potent neuroprotective e ects of AM-36 recently found in a stroke model in conscious rats.

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Section: A B C D E Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Callaway¹,

Beart²,

Jarrott³

et al. 2001

British J Pharmacology

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“…Notably, in several pathological conditions (e.g. brain ischemia; Linnik et al, 1995;Beilharz et al, 1995;Portera-Cailliau et al, 1995;Charriaut-Marlangue et al, 1996), liver damage by cytokines or toxins (Leist et al, 1995(Leist et al, , 1997b) demise can occur simultaneously by necrosis or apoptosis. Work in our laboratory and in collaboration with Dr SA Lipton and Dr S Orrenius has previously shown that the intensity of the same initial insult decides the prevalence of either apoptosis or necrosis (Dypbukt et al, 1994;Bonfoco et al, 1995).…”

Section: Energy Supply and Cell Death P Nicotera And M Leistmentioning

confidence: 99%

Energy supply and the shape of death in neurons and lymphoid cells

1997

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Apoptosis and necrosis are considered as conceptually distinct forms of cell death. Nevertheless, there is increasing evidence that classical apoptosis and necrosis represent only the extreme ends of a wide range of possible morphological and biochemical deaths. The two classical types of demise can occur simultaneously in tissues or cell cultures exposed to the same stimulus, and often the intensity of the same initial insult decides the prevalence of either apoptosis or necrosis. This suggests that, while some early events may be common to both types of cell death, a downstream controller may be required to direct cells towards the organised execution of apoptosis. We have recently shown that intracellular energy levels and mitochondrial function are rapidly compromised in necrosis, but not in apoptosis of neuronal cells. Then, we went on to show that pre-emptying human T cells of ATP switches the type of demise caused by two classic apoptotic triggers (staurosporin and CD95 stimulation) from apoptosis to necrosis. Conditions of controlled intracellular ATP depletion, which was obtained by blocking mitochondrial and/or glycolytic ATP generation, were used in combination with repletion of the cytosolic ATP pool with glucose to redirect the death program towards apoptosis or necrosis. At least two distinct steps, the typical nuclear degradation, and the expression of annexin V-recognisable determinants on the cell surface require sufficient ATP generation. This suggests that some upstream regulators of cell death may be common to both types of cell demise, whereas yet unknown downstream processes decide its shape and the implications for the neighbouring tissue.

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“…The precipitated DNA was analyzed on a 2% agarose gel. The experiment was repeated in three different groups (Linnik et al 1995).…”

Section: Dna Fragmentation Analysismentioning

confidence: 99%

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

Singh¹,

Upadhyay²,

Kumar³

et al. 2003

Journal of Endocrinology

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Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-x L and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-x L were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by downregulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.

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Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion

Cited by 150 publications

References 32 publications

Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Energy supply and the shape of death in neurons and lymphoid cells

Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

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