In vivo Binding of Nimodipine in the Brain: II. Binding Kinetics in Focal Cerebral Ischemia

Hogan, Matthew J.; Gjedde, Albert; Hakim, Antoine M.

doi:10.1038/jcbfm.1991.134

Cited by 20 publications

(11 citation statements)

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“…These results are consistent with our earlier observations of in vivo nimodipine binding in a model of irreversible focal ischemia (Hakim and Hogan, 199 1 ;Hogan et al, 1991). In that work increased nimodipine binding was first observed in regions with severe depression of CBF and was only later seen in regions the reperfused group (n = 11).…”

Section: Discussionsupporting

confidence: 92%

“…A blood sample was obtained at the time of decapitation, and 'H activity was determined using liquid scintillation counting. Metabolite concentration corrections following intravenous nimodipine administration have been previously determined in Sprague-Dawley rats (Hogan et al, 1991) and were used to calculate nimodipine concentrations in plasma and brain samples.…”

Section: Determination Of Nimodipine Bindingmentioning

confidence: 99%

“…We have previously demonstrated in a rat model that irreversible focal cerebral ischemia increased in vivo binding of the 1,4-dihydropyridine calcium channel antagonist nimodipine to ischemic brain tissue (Hakim and Hogan, 1991;Hogan et al, 1991). The affinity of the L-type VSCC to bind 1,4-dihydropyridines increases in depolarized cell membranes (Bean, 1984;Kokubun et al, 1986).…”

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confidence: 99%

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Reversibility of Nimodipine Binding to Brain in Transient Cerebral Ischemia

Hogan¹,

Hakim²

1992

Journal of Neurochemistry

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Using autoradiography, we have measured the in vivo binding of [3H]nimodipine to brain in a rat model of reversible cerebral ischemia. Ischemia was induced by simultaneous occlusion of the middle cerebral artery (MCA) and ipsilateral common carotid artery by microaneurysm clips. Rats were studied after 15 min of ischemia (ischemic group) or after 45 min of reperfusion following 15 min of ischemia (reperfused group). Regional cerebral blood flow (CBF) was determined autoradiographically using [14C]iodoantipyrine in both ischemic (n = 6) and reperfused (n = 6) groups. During ischemia blood flow in the territory of the MCA was depressed and recovered to normal only in the distal territory of the MCA following reperfusion. [3H]Nimodipine binding in the ischemic group (n = 12) was elevated in ischemic brain regions and declined significantly (p < 0.01) in these regions in the reperfused group (n = 11). The ratio of the volume of cortex showing increased binding to the total volume of the forebrain was 0.113 +/- 0.025 (mean +/- SD) in the ischemic group and declined to 0.080 +/- 0.027 following reperfusion (p < 0.005). In general, infarct was only observed in regions showing persistent elevation of nimodipine binding following reperfusion as determined by histology performed in a separate group of rats (n = 8) after 24 h of reperfusion. We conclude that increased nimodipine binding to ischemic tissue is initially reversible with prompt reestablishment of CBF and is a sensitive indicator of early and reversible ischemia-induced cerebral dysfunction.

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Section: Discussionsupporting

confidence: 92%

Section: Determination Of Nimodipine Bindingmentioning

confidence: 99%

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confidence: 99%

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Reversibility of Nimodipine Binding to Brain in Transient Cerebral Ischemia

Hogan¹,

Hakim²

1992

Journal of Neurochemistry

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“…It has been shown that after 5 minutes of ischemia the VSCCs are open, Ca ++ moves intracellularly, and specific binding of the VSCC antagonists increases in severely affected ischemic regions. 15 In vivo binding of dihydropyridine Ca ++ antagonists in ischemic brain tissue is to the high-affinity binding state of the L-type VSCC 19 that occurs in depolarized cell membranes. 39 The physiological importance of this binding is debatable; however, it is possible that this process is related to the improvement in histological outcome observed following early treatment with dihydropyridine Ca ++ antagonists.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of brain injury and reduction of neuron-specific enolase by nicardipine in systemic circulation following focal ischemia and reperfusion in a rat model

Kittaka¹,

Giannotta²,

Zelman³

et al. 1997

Journal of Neurosurgery

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A reversible middle cerebral artery occlusion was performed in rats to determine whether nicardipine, a dihydropyridine voltage-sensitive Ca++ channel (VSCC) antagonist, exerts neuroprotective effects when administered 10 minutes following an ischemic insult, and if it does, whether this is due to its vasodilatory action and effect on cerebral blood flow (CBF) or to direct blockade of Ca++ entry into ischemic brain cells. An increase in the intracellular calcium, [Ca++]i, plays a major role in neuronal injury during cerebral ischemia. Although a large amount of Ca++ enters neurons through the VSCC during ischemia, inconsistent neuroprotective effects have been reported with the antagonists of the VSCC. An intraperitoneal injection of nicardipine (1.2 mg/kg) was administered to rats 10 minutes after the onset of ischemia, and 8, 16, and 24 hours after occlusion. Cortical CBF was determined by laser-Doppler flowmetry. Neurological and neuropathological examinations were performed after 72 hours. Neuron-specific enolase, a specific marker for the incidence of neuronal injury, was measured in plasma. The CBF and other physiological parameters were not affected by nicardipine during occlusion or reperfusion. However, nicardipine treatment significantly improved motor neurological outcome by 29%, and the infarction and edema volume in the pallium as well as the edema volume in the striatum were significantly reduced by 27%, 37%, and 52%, respectively. Nicardipine also reduced the neuron-specific enolase plasma levels by 50%, 42%, and 59% at 24, 48, and 72 hours after the occlusion, respectively. It is concluded that nicardipine may attenuate focal ischemic brain injury by exerting direct neuroprotective and antiedematous effects that do not depend on CBF.

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“…Most clinical trials focus on nimodipine, but others like nilvadipine have also been studied. Nimodipine (Suwelack et al, 1985;Hogan et al, 1991;Wang et al, 2006) and nilvadipine (Takakura et al, 1992) penetrate the blood-brain barrier effectively, and therefore are convenient calcium channel blockers for testing a direct neuroprotective effect. …”

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confidence: 99%

Calcium channel blockers and dementia

Nimmrich

Eckert

2013

British J Pharmacology

133

104

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Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. AbbreviationsAβ, amyloid-β; AD, Alzheimer's disease; APP, amyloid precursor protein; LTP, long-term potentiation; VaD, vascular dementia; VGCC, voltage-gated calcium channel IntroductionDementia affects 7% of the population over the age of 65, and then progressively increases with age Rocca et al., 1991). Alzheimer's disease (AD) is the leading cause of dementia, followed by vascular dementia (VaD). AD is characterized by three neuropathological hallmarks: extracellular aggregates of amyloid-β (Aβ) peptide (amyloid plaques), neurofibrillary tangles and synaptic loss (Bell and Cuello, 2006). According to the amyloid cascade hypothesis, overproduction of the hydrophobic peptide Aβ 1-42 is the basis for AD pathology (Hardy and Higgins, 1992).Aggregation of Aβ 1-42 is thought to occur in several steps via fibrils, which are finally deposited as amyloid plaques. It was suggested that an alternative pathway leads to the generation of stable oligomeric aggregates, Aβ oligomers (Gellermann et al., 2008;Yu et al., 2009b), which are considered to mediate the toxic Aβ effects (Hardy and Selkoe, 2002). Different forms of Aβ oligomers can be generated synthetically (e.g. Stine et al., 2003; Barghorn et al., 2005) or are harvested from cell lines (Walsh et al., 2002). These preparations were tested in vitro and in animal models, and the results lead to the generally accepted view that Aβ oligomers specifically disturb synaptic function . Constant impairment of neurotransmission leads to a retraction of synapses, which is then evident in the autopsy of AD brains (for a review, see Nimmrich a...

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In vivo Binding of Nimodipine in the Brain: II. Binding Kinetics in Focal Cerebral Ischemia

Cited by 20 publications

References 13 publications

Reversibility of Nimodipine Binding to Brain in Transient Cerebral Ischemia

Reversibility of Nimodipine Binding to Brain in Transient Cerebral Ischemia

Attenuation of brain injury and reduction of neuron-specific enolase by nicardipine in systemic circulation following focal ischemia and reperfusion in a rat model

Calcium channel blockers and dementia

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