The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).

Summary:It is estimated 20-25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P-glycoprotein (P-gp) and others ABC transporters as multidrug-resistance-associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P-gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P-gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P-pg detection in vesselrelated cells and later additional P-gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, was in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P-gp expression in excretory organs suggests that P-gp have a central role in drug elimination.Persistent low levels of AEDs in plasma and P-gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99m Tc-hexakis-2-methoxyisobutylisonitrile ( 99m Tc-MIBI) (a P-gp substrate), and the surgically treated cases showed Pgp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp overexpression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P-gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure-affected P-gp-positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P-gp-expressed cells that exhibit lower membrane potential ( ψ 0 = −10 to -20) compared to normal physiological ψ 0 of -60 mV. Under this situation and irrespective to the P-gp pharmacoresistant property or type of drug treatment selected, P-gp-expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE. Key Words: Refractory epilepsy-MDR-BCRP-MVP99m Tc-MIBI.

J. Neurochem. (2010) 112, 854–869. Abstract Sleep apnea (SA) can be effectively managed in humans but it is recognized that when left untreated, SA causes long‐lasting changes in neuronal circuitry in the brain. Recent neuroimaging studies gave suggested that these neuronal changes are also present even in patients successfully treated for the acute effects of SA. The cellular mechanisms that account for these changes are not certain but animal models of intermittent hypoxia (IH) during sleep have shown neuronal death and impairment in learning and memory. Reactive gliosis has a drastic effect on neuronal survival and circuitry and in this study we examined the neuro‐glial response in brain areas affected by SA. Glial and neuronal alterations were analyzed after 1, 3, 5 and 10 days of exposure to IH (8 h/day during the sleep phase, cycles of 6 min each, 10–21% O2) and observed significant astroglial hyperplasia and hypertrophy in parietal brain cortex and hippocampus by studying gliofibrillary acidic protein, Vimentin, S100B and proliferating cell nuclear antigen expression. In addition, altered morphology, reduced dendrite branching and caspase activation were observed in the CA‐1 hippocampal and cortical (layers IV–V) pyramidal neurons at short exposure times (1–3 days). Surprisingly, longer exposure to IH reduced the neuronal death rate and increased neuronal branching in the presence of persistent reactive gliosis. Up‐regulation of hypoxia inducible factor 1 alpha (HIF‐1α) and mdr‐1, a HIF‐1α target gene, were observed and increased expression of receptor for advanced end glycated products and its binding partner S100B were also noted. Our results show that a low number of hypoxic cycles induce reactive gliosis and neuronal death whereas continuous exposure to IH cycles reduced the rate of neuronal death and induced neuronal branching on surviving neurons. We hypothesize that HIF‐1α and S100B glial factor may improve neuronal survival under hypoxic conditions and propose that the death/survival/re‐growth process observed here may underlie brain circuitry changes in humans with SA.

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