Reader Comments

Post a new comment on this article

P-glycoprotein (Pgp), alkaline phosphatase modulators and hypothalamic-pituitary-adrenal (HPA) axis regulation

Posted by isabelaz on 22 Apr 2009 at 12:59 GMT

This model-based therapeutic proposal for correction of hypothalamic-pituitary-adrenal axis dysfunction [1] is highly interesting and makes much sense. As a matter of fact, cortisol levels analysis in the context of depression and other pathologies has been puzzling researchers for a long time [2,3], a simple, linear model clearly not fitting.
Among discussed methods to reduce cortisol action upon central glucocorticoid receptors as a way to reinstall an adequate production of ACTH, the authors mention Pgp, an exporter of cortisol at the blood-brain-barrier. We think this is a highly convenient mechanism to explore, as there is a putative way to increase Pgp activity through an increase of alkaline phosphatase activity [4]. Polyphenols, beta-estradiol and progesterone were shown to increase that enzyme activity at the level of blood-brain-barrier cells [5]. Among these substances, progesterone was the most potent, showing a concentration-dependent effect. This is interesting, as depression, a pathology with a relationship with cortisol, tends to decrease along pregnancy [6], i.e. in parallel with progesterone increase, and is a frequent problem at the post-partum period [6,7], when progesterone levels are abruptly reduced.


[1] Ben-Zvi A, Vernon SD, Broderick G (2009) Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction. PLoS Comput
Biol 5(1): e1000273. doi:10.1371/journal.pcbi.1000273

[2] Henry JP (1997) Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand 161, suppl 640: 10-25.

[3] Olsson T, Sapolsky R (2006) The healthy cortisol response. In: Bengt B Arnetz, Rolf Ekman (Eds), Stress in health and disease. Wiley-VCH, pp. 214-225.

[4] Martel F, Martins MJ, Hipólito-Reis C, Azevedo I (1996) Inward transport of [3H]-1-phenylpyridinium in rat isolated hepatocytes: putative involvement of a Pglycoprotein
transporter. Br J Pharmacol 119:1519-1524.

[5] Calhau C, Martel F, Pinheiro-Silva S, Pinheiro H, Soares-da-Silva P, Hipólito-Reis C, Azevedo I (2002) Modulation of insulin transport in rat brain microvessel
endothelial cells by an ecto-phosphatase activity. J Cell Biochem 84: 389-400.

[6] Brooks J, Nathan E, Speelman C, Swalm D, Jacques A, Doherty D (2009) Tailoring screening protocols for perinatal depression: prevalence of high risk across obstetric services in Western Australia. Arch Womens Ment Health 12: 105-112.

[7] Vesga-López O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS (2008) Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry 65: 805-815.

Conceição Calhau, Isabel Azevedo
Depart Biochemistry, Fac. Medicine, University of Porto, Portugal

No competing interests declared.