Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

2015
Authors
Popović, MarjanStanojević, Željka
Tosic, Jelena
Isaković, Aleksandra

Paunović, Verica
Petricevic, Sasa
Martinovic, Tamara

Ciric, Darko
Kravić-Stevović, Tamara

Šoškić, Vukić

Kostić Rajačić, Slađana

Shakib, Kaveh

Bumbasirevic, Vladimir
Trajković, Vladimir

Article (Published version)

Metadata
Show full item recordAbstract
Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D-2/5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]- picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)ethyl]- phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D-2 and 5-HT1A receptors. The protectionwas retainedif treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, T(H)1 cytokine IFN-gamma, T(H)17 cytokine IL-17, as well... as the signature transcription factors of T(H)1 (T-bet) and T(H)17 (ROR gamma t) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic proteinactivated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease inCNS inflammation.
Keywords:
apoptosis / arylpiperazines / CNS inflammation / neuroprotection / oligodendrocytesSource:
Journal of Neurochemistry, 2015, 135, 1, 125-138Publisher:
- Wiley, Hoboken
Projects:
- Modulation of intracellular energy balance-controlling signalling pathways in therapy of cancer and neuro-immuno-endocrine disorders (RS-41025)
- ProteoSysAG (Mainz, Germany)
DOI: 10.1111/jnc.13198
ISSN: 0022-3042
PubMed: 26083644