Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis

Abstract

Although melatonin is mainly produced by the pineal gland, an increasing number of extra-pineal sites of melatonin synthesis have been described. We previously demonstrated the existence of bidirectional communication between the pineal gland and the immune system that drives a switch in melatonin production from the pineal gland to peripheral organs during the mounting of an innate immune response. In the present study, we show that acute neuroinflammation induced by lipopolysaccharide (LPS) injected directly into the lateral ventricles of adult rats reduces the nocturnal peak of melatonin in the plasma and induces its synthesis in the cerebellum, though not in the cortex or hippocampus. This increase in cerebellar melatonin content requires the activation of nuclear factor kappa B (NF-κB), which positively regulates the expression of the key enzyme for melatonin synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Interestingly, LPS treatment led to neuronal death in the hippocampus and cortex, but not in the cerebellum. This privileged protection of cerebellar cells was abrogated when G-protein-coupled melatonin receptors were blocked by the melatonin antagonist luzindole, suggesting that the local production of melatonin protects cerebellar neurons from LPS toxicity. This is the first demonstration of a switch between pineal and extra-pineal melatonin production in the central nervous system following a neuroinflammatory response. These results have direct implications concerning the differential susceptibility of specific brain areas to neuronal death.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-013-0686-4) contains supplementary material, which is available to authorized users.

Efeito da melatonina sobre a viabilidade de células granulares de cerebelo em cultura depende do contexto celular

“…Por outro lado, o tecido cerebral apresenta a maquinaria molecular necessária para produzir melatonina (Gaudet et al, 1991;Uz et al, 2002;Jimenez-Jorge et al, 2006) e existem evidências de que esta produção seja feita por células da glia, já que expressam AA-NAT (Liu et al, 2007;Tan et al, 2010;Pinato et al, 2013). A importância dos altos níveis de melatonina encontrados no SNC pode estar relacionada à função neuroprotetora da melatonina (Hardeland, 2012).…”

“…A síntese de melatonina por células imunocompetentes ativadas por agentes pró-inflamatórios foi demonstrado em linfócitos (Carrilo-Vico et al, 2004;, macrófagos (Martins et al, 2004;Muxel et al, 2012;Pires-Lapa et al, 2013), células mono e polimorfonucleares de colostro (Pontes et al, 2006(Pontes et al, , 2007, timócitos (Naranjo et al, 2007), mastócitos (Maldonado et al, 2010) e células da glia (Pinato et al, 2013). A produção de melatonina por macrófagos do colostro é bloqueada ao ser inibida a translocação nuclear do NF-κB (Pires-Lapa et al,…”

“…O cerebelo é capaz de sintetizar melatonina por um mecanismo dependente de NF-κB (Pinato et al, 2013). A injeção de LPS no ventrículo lateral de rato reduz o pico noturno de melatonina no plasma e induz a sua síntese no cerebelo, mas não no córtex e no hipocampo.…”

“…de LPS (Pinato et al, 2013). A expressão da enzima chave na síntese de melatonina, AA-NAT foi detectada por imunocitoquímica.…”

“…Na cultura de células granulares de cerebelo de camundongo Imbesi e colaboradores (2008) (Pinato et al, 2013).…”