Minocycline provides protection against beta-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex.
Minocycline is a semi-synthetic second-generation tetracycline known to improve cognition in amyloid precursor protein transgenic mice. Whether it can protect the somatostatin (SRIF) receptor-effector system, also involved in learning and memory, from alterations induced by chronic i.c.v. infusion of beta-amyloid peptide (Abeta)(25-35) is presently unknown. Hence, in the present study, we tested the effects of minocycline on the SRIF signaling pathway in the rat temporal cortex. To this end, male Wistar rats were injected with minocycline (45 mg/kg body weight) i.p. twice on the first day of treatment. On the following day and during 14 days, Abeta(25-35) was administered i.c.v. via an osmotic minipump connected to a cannula implanted in the left lateral ventricle (300 pmol/day). Minocycline (22.5 mg/kg, i.p.) was injected once again the last 2 days of the Abeta(25-35) infusion. The animals were killed by decapitation 24 h after the last drug injection. Our results show that minocycline prevents the decrease in SRIF receptor density and somatostatin receptor (sst) 2 expression and the attenuated capacity of SRIF to inhibit adenylyl cyclase (AC) activity, alterations present in the temporal cortex of Abeta(25-35)-treated rats. Furthermore, minocycline blocks the Abeta(25-35)-induced decrease in phosphorylated cyclic AMP (cAMP) response element binding protein (p-CREB) content and G-protein-coupled receptor kinase 2 (GRK) protein expression in this brain area. Altogether, the present data demonstrate that minocycline in vivo provides protection against Abeta-induced impairment of the SRIF signal transduction pathway in the rat temporal cortex and suggest that it may have a potential as a therapeutic agent in human Alzheimer's disease, although further studies are warranted.
Burgos-Ramos
E
E
Departamento de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Puebla-Jiménez
L
L
Arilla-Ferreiro
E
E
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D007150:Immunohistochemistry; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000187:drug effects* / Q000378:metabolism; D013702:Temporal Lobe / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017481:Receptors, Somatostatin; D013004:Somatostatin; D008911:Minocycline