Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model

Höcht, Christián; Lazarowski, Alberto; Gonzàlez, Nèlida N.; Auzmendi, Jerónimo; Opezzo, Javier A.W.; Bramuglia, Guillermo F.; Taira, Carlos A.; Girardi, Elena

doi:10.1016/j.neulet.2006.11.075

Cited by 56 publications

(27 citation statements)

References 28 publications

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“…In this regard, we have previously documented the persistent high neuronal P-gp expression during 20 days after focal cortical devascularization ) and, similarly, we also observed high neuronal P-gp expression being detected 5 days after experimental focal hypoxia induced by direct CoCl 2 cortical injection, suggesting that it could be a new obstacle for pharmacological neuroprotection in stroke (Lazarowski et al 2007a). Furthermore, similar high neuronal P-gp expression induced by frequent convulsive stress was associated with altered hippocampal pharmacokinetics of phenytoin and progressively acquired pharmacoresistant phenotype Höcht et al 2007;Lazarowski et al 2007b).…”

Section: Introductionsupporting

confidence: 82%

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Merelli

Caltana

Girimonti³

et al. 2010

Neurotox Res

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Stroke is a major human health problem inducing long-term disability without any efficient therapeutic option being currently available. Under hypoxia, hypoxia-inducible factor-1α (HIF-1α) activates several genes as erythropoietin receptor (Epo-R) related with O(2) supply, and the multidrug-resistance gene (MDR-1) related with drug-refractory phenotype. Brain cortical injection of CoCl(2) produces focal hypoxia-like lesion with neuronal and glial alterations, as well as HIF-1α stabilization and MDR-1 overexpression. Intranasal (IN) drug delivery can by-pass blood-brain barrier (BBB) where MDR-1 is normally expressed. We evaluated the effects of IN-rHu-Epo administration on spontaneous motor activity (SMA) and the brain pattern expression of HIF-1α, MDR-1, and Epo-R in our cobalt-induced hypoxia model. Adult male Wistar rats were injected by stereotaxic surgery in frontoparietal cortex, with CoCl(2) (2 μl-50 mM; n = 20) or saline (controls; n = 20). Ten rats of each group were treated with IN-rHu-Epo 24 U or IN-saline. In addition, erythropoietic stimulation was evaluated by reticulocytes (Ret) account during three consecutive days, after intraperitoneal (i.p.)-recombinant-human Epo (rHu-Epo) (950 U; n = 6) or IN-rHu-Epo (24 U; n = 6) administration. SMA was evaluated by open field and rotarod tests, before and after surgical procedures during five consecutive days. Histological and immunostaining studies of HIF-1α, MDR-1, and Epo-R were performed on brain slides. A significant difference in SMA was observed in the hypoxic rats of IN-rHu-Epo-administered group as compared with Co-Saline-treated subjects and controls (p < 0.001). HIF-1α, EPO-R, and MDR-1 were overexpressed in the hypoxic cortex areas, while in contralateral hemisphere or controls, they were negatives. Reticulocytes were only increased in intraperitoneal (i.p.)-rHu-Epo-administered group. In spite of MDR-1 overexpression being detected in neurons, the coexpression of Epo-R could explain the positive effects observed on SMA of IN-rHu-Epo-administered group.

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Section: Introductionsupporting

confidence: 82%

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Merelli

Caltana

Girimonti³

et al. 2010

Neurotox Res

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“…We suggest that according with the recently defined "neurovascular unit" [41] this critical role for mdr-1 gene should be extended to other hypoxic cells, as astrocytes and neurons expressing P-gp as observed in our experiment. Concerning the functionality of the P-gp, it was recently demonstrated that Nimodipine restores the altered hippocampal phenytoin pharmacokinetics and seizures control [42] in a refractory epilepsy model with high P-gp neuronal expression described by our group [14].…”

Section: Discussionmentioning

confidence: 81%

Neuronal mdr-1 gene expression after experimental focal hypoxia: A new obstacle for neuroprotection?

Lazarowski

Caltana

Merelli

et al. 2007

Journal of the Neurological Sciences

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“…increased the latency but did not prevent kainic acid-induced epileptic activity (81). Recently, it has been shown that nimodipine could reverse refractory epileptic phenotype to phenytoin treatment by modifying altered hippocampal phenytoin pharmacokinetics (82). These data collectively indicate that nimodipine could represent an effective strategy to decrease pharmacoresistance to phenytoin antiepileptic treatment.…”

Section: Anticonvulsant Effectsmentioning

confidence: 99%

Nimodipine and Its Use in Cerebrovascular Disease: Evidence from Recent Preclinical and Controlled Clinical Studies

Tomassoni

Lanari

Silvestrelli

et al. 2008

Clinical and Experimental Hypertension

118

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Nimodipine is a 1,4-dihydropyridine-derivative Ca(2+)-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca(2+)-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospasm in SAH patients.

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Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model

Cited by 56 publications

References 28 publications

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl2 in Rats

Neuronal mdr-1 gene expression after experimental focal hypoxia: A new obstacle for neuroprotection?

Nimodipine and Its Use in Cerebrovascular Disease: Evidence from Recent Preclinical and Controlled Clinical Studies

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