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- Caruso, Carla, et al.
(författare)
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Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon-gamma in astrocytes
- 2007
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 148:10, s. 4918-4926
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-MSH exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western blot analysis. alpha-MSH (5 microm) reduced the nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) induced by bacterial lipopolysaccharide (LPS, 1 microg/ml) plus interferon-gamma (IFN-gamma, 50 ng/ml) in cultured astrocytes after 24 h. alpha-MSH also attenuated the stimulatory effect of LPS/IFN-gamma on prostaglandin E(2) release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the antiinflammatory effects of alpha-MSH, suggesting a MC4R-mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN-gamma treatment reduced cell viability, increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and activated caspase-3. alpha-MSH prevented these apoptotic events, and this cytoprotective effect was abolished by HS024. LPS/IFN-gamma decreased Bcl-2, whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. Alpha-MSH produced a shift in Bax/Bcl-2 ratio toward astrocyte survival because it increased Bcl-2 expression and also prevented the effect of LPS/IFN-gamma on Bax and Bcl-2 expression. In summary, these findings suggest that alpha-MSH, through MC4R activation, attenuates LPS/IFN-gamma-induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN-gamma-induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.
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| 2. |
- Gonzalez, Patricia Verónica, et al.
(författare)
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Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors
- 2009
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 23:6, s. 817-822
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1beta (IL-1beta) significantly influences memory consolidation. Treatments that raise the level of IL-1beta in the brain, given after training, impair contextual fear conditioning. The melanocortin alpha-MSH exerts potent anti-inflammatory actions by physiologically antagonizing the effect of pro-inflammatory cytokines. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, with MC3R and MC4R predominating in the central nervous system. The present experiments show that injection of IL-1beta (5 ng/0.25 microl) in dorsal hippocampus up to 15 min after training decreased freezing during the contextual fear test. The treatment with IL-1beta (5 ng/0.25 microl) 12h after conditioning cause amnesia when animals were tested 7 days post training. Thus, our results also demonstrated that IL-1beta can influence persistence of long-term memory. We determined that animals previously injected with IL-1beta can acquire a new contextual fear memory, demonstrating that the hippocampus was not damaged. Treatment with alpha-MSH (0.05 microg/0.25 microl) blocked the effect of IL-1beta on contextual fear memory. Administration of the MC4 receptor antagonist HS014 (0.5 microg/0.25 microl) reversed the effect of alpha-MSH. However, treatment with gamma-MSH (0.5 microg/0.25 microl), an MC3 agonist, did not affect IL-1beta-induced impairment of memory consolidation. These results suggest that alpha-MSH, through central MC4R can inhibit the effect of IL-1beta on memory consolidation.
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