N-Ethylmaleimide increases cerebrospinal fluid secretion in young but not old sheep

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University of Cambridge (2004) J Physiol 555P, PC43

Communications: N-Ethylmaleimide increases cerebrospinal fluid secretion in young but not old sheep

R.L. Chen, N. Kassem, M.B. Segal and J.E. Preston

Institute of Gerontology and Centre for Neuroscience Research, King's College London, 150 Stamford Street, London SE1 9NN, UK

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Cerebrospinal fluid (CSF) secretion by the choroid plexuses (CP) decreases during normal ageing in rat, human and sheep (Preston, 2001). The ability to stimulate CSF secretion during ageing has potential clinical benefits, to prevent accumulation of toxins (e.g. amyloid-β) and facilitate hormone and bio-active peptide distribution in the brain. We studied the effect of N-ethylmaleimide (NEM), a K+, Cl– co-transport stimulator (Kirk, 1991), on CSF secretion in the in vitro perfused ovine lateral cerebral ventricle CPs.

Six pairs of young (1-2 years) and old (7-8 years) sheep were anaesthetised with I.V. thiopentone sodium (20 mg kg-1), killed by cervical dislocation, their brains removed and CPs perfused in situ via the choroidal artery with albumin Ringer. Procedures were in accordance with Animals (Scientific Procedures) Act 1986 and animals humanely killed. Secretion rates were measured by colourimetric analysis of perfusate and effluent (Preston and Segal, 1990). Ion extraction (36Cl 0.1 MBq 100 ml-1 or 22Na 0.05 MBq 100 ml-1) was calculated from the arterio-venous difference in activity, accounting for the extracellular marker 14C-mannitol (0.2 MBq 100 ml-1). NEM (0.5 mM) was added to perfusate and CSF after 30 min perfusion, for an additional 60 min. NEM had significant effects on young CP, increasing CSF secretion rates from 47.2 ± 13 to 91.3 ± 26 ml min-1.g-1, (mean ± S.E.M., P < 0.05 paired student t test). In addition, there was an increase in extraction of 36Cl from 8.8 % ± 4 % to 18 % ± 3 %, (n = 3, P < 0.05) however, there was no effect of NEM on 22Na extraction in young CP. In the old CP, neither CSF secretion rate nor ion extraction (36Cl or 22Na) was altered after adding NEM.

This study has demonstrated that in the young sheep there is a functional correlation between CSF secretion rate and Cl– extraction in this model, however, the lack of response in old CP indicates an inability to up-regulate Cl– transport and may help explain the reduced CSF secretory ability in old animals.

This work was supported by the BBSRC.

Where applicable, experiments conform with Society ethical requirements.

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