Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands.

Telomeres of human chromosomes contain a G-rich 3'-overhang that adopts an intramolecular G-quadruplex structure in vitro which blocks the catalytic reaction of telomerase. Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase and can therefore act as antitumor agents. We have identified by Fluorescence Resonance Energy Transfer a new series of quinoline-based G-quadruplex ligands that also exhibit potent and specific anti-telomerase activity with IC50 in the nanomolar concentration range. Long term treatment of tumor cells at subapoptotic dosage induces a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of the senescent cell phenotype (large size and expression of beta-galactosidase activity). Our data show that a G-quadruplex interacting agent is able to impair telomerase function in a tumor cell thus providing a basis for the development of new anticancer agents.

Riluzole reduces brain lesions and improves neurological function in rats after a traumatic brain injury.

Riluzole (2-amino 6-trifluoromethoxy-benzothiazole) was studied in a rat model of traumatic brain injury (TBI) induced by a fluid percussion applied laterally to the right parietal cortex. Study I: vehicle or riluzole (4 or 8 mg/kg) was administered 15 min (i.v.), 6 h and 24 h (s.c.), after TBI. Brain lesions were quantified 1 week after insult. Riluzole significantly reduced the size of TBI-induced lesions by approximately 44% with either dose regime (P < 0.05). Study II: vehicle or riluzole (8 mg/kg) was administered 15 min (i.v.), 6 h (i.p.) and then twice daily (i.p.) for 6 days, after injury. One, 2 and 3 weeks after TBI, a neurological examination was performed. Control injured rats had a significant neurological deficit at 1, 2 and 3 weeks (P < 0.001). Riluzole treatment did not modify the neurological status evaluated for the first 2 weeks after TBI. However at 3 weeks, riluzole significant improved the neurological function of injured rats (P < 0.05). These results suggest that riluzole may be beneficial in the clinical treatment of TBI. The protective action of riluzole may result from (i) stabilization of the inactivated state of voltage-dependent sodium channels, (ii) indirect action on the glutamatergic pathway, and/or (iii) indirect neurotrophic effect.