Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents

Rataud, J.; Debarnot, Florence; Mary, Véronique; Pratt, Jeremy; Stutzmann, Jean‐Marie

doi:10.1016/0304-3940(94)90652-1

Cited by 103 publications

(46 citation statements)

References 26 publications

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“…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 . Pharmacological modulation of voltage-sensitive sodium channels is considered to be a rational and e ective therapeutic strategy against neuronal damage in cerebral ischaemia (Carter, 1998;Rataud et al, 1994). Sodium in¯ux is an important initiating event leading to anoxic damage and a cascade of cellular events (Stys et al, 1992).…”

Section: A B C D E Fmentioning

confidence: 99%

“…ROS, which are well known to induce lipid peroxidation, DNA damage and alterations in enzyme activation, contribute substantially to neuronal death in cerebral ischaemia (Dirnagl et al, 1999;Kuroda et al, 1997). 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).…”

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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“…3,10,18,21,22 The aim of the present study was to determine the effects of presynaptic glutamate release inhibition on SCI by evaluating oxidative stress parameters and the ultrastructural integrity of the spinal cord by the use of electron microscopy.…”

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confidence: 99%

“…Lamotrigine reduces infarct volume and lipid peroxidation and improves neurological outcome after focal and global cerebral ischemia. 3,18,20,21 The most important neuroprotective action of lamotrigine is inhibition of overstimulation of glutamate receptors by decreasing presynaptic glutamate release in pathological states. Moreover, cell culture studies demonstrated that lamotrigine has direct antagonistic effects on Ca channels in addition to Na + channels.…”

mentioning

confidence: 99%

“…Neuroprotective effects of 50 mg/kg lamotrigine have been shown in previous studies, with no significant adverse effects reported. Rataud et al 18 reported that animals treated with 50 mg/kg but not 25 mg/ kg lamotrigine showed significant reduction in the size of cortex infarction in focal cerebral ischemia. In the study by Bacher and Zornow, 3 the authors reported that, in a transient global cerebral ischemia model, 50 mg/kg lamotrigine was more effective in inhibiting the glutamate accumulation than 20 mg/kg lamotrigine.…”

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confidence: 99%

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Ultrastructure protection and attenuation of lipid peroxidation after blockade of presynaptic release of glutamate by lamotrigine in experimental spinal cord injury

Tufan

Öztanir²,

Ofluoglu

et al. 2008

FOC

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Object Lamotrigine is an antiepileptic drug that inhibits presynaptic voltage-gated sodium channels and reduces the presynaptic release of glutamate in pathological states. Neuroprotective effects of this drug have already been demonstrated in cerebral ischemia models. The aim of the present study was to determine the effects of presynaptic glutamate release inhibition on experimental spinal cord injury (SCI). Methods A total of 66 adult Wistar rats were randomly allocated into 6 groups. Group I was the control group used to obtain normal blood samples and spinal cord specimens. Spinal cord injury was introduced by using the extradural clip compression technique, but no medication was given to Group II (trauma group) rats. Group III was treated with vehicle, and the same amount of dimethyl sulfoxide used in treatment groups was administered to these rats. A dose of 50 mg/kg lamotrigine was administered intraperitoneally to Group IV (pretreatment), Group V (peritreatment), and Group VI (posttreatment) rats 30 minutes before, during, and 30 minutes after SCI, respectively. Oxidative stress parameters and transmission electron microscopic findings were examined. Results Blockade of presynaptic release of glutamate by lamotrigine treatment yielded protective effects on the spinal cord ultrastructure even when administered after the SCI, but it prevented oxidative stress only when it was administered before or during the SCI. Conclusions Currently, no available agent has been identified, that can block all the glutamate receptors at the same time. To prevent excitotoxicity in SCI, inhibiting glutamate release from the presynaptic buttons instead of blocking the postsynaptic glutamate receptors seems to be a more rational approach. Further research, such as neurobehavioral assessment, is warranted to demonstrate the probable neuroprotective effects of presynaptic glutamate release inhibition in SCI.

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Vinpocetine for cognitive impairment and dementia

Szatmári

Whitehouse

2003

Cochrane Database of Systematic Reviews

107

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Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents

Cited by 103 publications

References 26 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

Ultrastructure protection and attenuation of lipid peroxidation after blockade of presynaptic release of glutamate by lamotrigine in experimental spinal cord injury

Vinpocetine for cognitive impairment and dementia

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