Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Mitochondrial benzodiazepine receptors and ageing

Two complementary therapeutic strategies to promote successful aging have been explored within the frame of this project:
- The systemic administration of steroids and

- The stimulation of the local synthesis of neurosteroids in the nervous system by ligands of the mitochondrial benzodiazepine receptor (MBR).

Indeed, steroids present in nervous tissues originate either from the steroidogenic endocrine glands (gonads and adrenal glands) as they easily cross the blood-brain barrier, or from local synthesis. It is in fact now well established that some steroids, which have been named "neurosteroids", can be synthesized in the brain, spinal cord and peripheral nerves by neurons and glial cells.

A rate-limiting step in steroid synthesis is the transport of cholesterol from the outer to the inner mitochondrial membrane, where the cytochrome P450scc, enzyme that converts cholesterol to pregnenolone, is located. The MBR is a protein of the outer mitochondrial membrane, necessary for the intramitochondrial transport of cholesterol. The administration of MBR agonists has been shown to increase the synthesis of steroid hormones by the gonads and of neurosteroids within the nervous system.

It is important to note that the MBR, also called "peripheral benzodiazepine receptor" (PBR), is distinct from the classical benzodiazepine sites located on GABAA receptors: the MBR it is not associated with GABAA receptors and recognizes selective ligands.

The administration of the MBR agonist allows to protect neurons and to reverse age-related abnormalities of myelin sheaths. Thus, hilar neurons of the hippocampus can be protected against excitotoxic injury by the administration of Ro5-4864. Activation of the MBR receptor has also beneficial effects on ageing-associated degeneration of the rat sciatic nerve, increasing the total number of myelinated fibers and decreasing the percentage of fibers with myelin decompaction.

All these effects were blocked by the simultaneous treatment with the MBR antagonist PK-11195. The effects of the MBR ligands apparently did not involve changes in neurosteroid levels and are distinct from those previously observed in response to the systemic administration of progestins.

Attempts to stimulate the synthesis of neurosteroids by MBR ligands in nervous tissues of old rats have not been successful so far, suggesting an impairment of MBR-induced steroidogenesis in old animals. There is an obvious need for more efficient MBR ligands. Two novel MBR ligands have been studied in collaboration with two industrial partners.

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Institut national de la santé e de la recherche médicale
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