Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats. (15th July 2015)

• Record Type: Journal Article
• Authors: Popovic, Marjan; Stanojevic, Zeljka; Tosic, Jelena; Isakovic, Aleksandra; Paunovic, Verica; Petricevic, Sasa; Martinovic, Tamara; Ciric, Darko; Kravic‐Stevovic, Tamara; Soskic, Vukic; Kostic‐Rajacic, Sladjana; Shakib, Kaveh; Bumbasirevic, Vladimir; Trajkovic, Vladimir
• Is Part Of: Journal of neurochemistry. Volume 135:Number 1(2015:Oct.)
• Page Start: 125
• Page End: 138
• Publication Date: 2015-07-15
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13198
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc13198-abs-0001"> <title>Abstract</title> <sec id="jnc13198-sec-1001" sec-type="section"> <p>Arylpiperazine‐based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D<sub>2</sub>/5‐HT<sub>1A</sub> ligands, N‐{4‐[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl}‐phenyl]‐picolinamide (<bold>6a</bold>) and N‐{3‐[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐picolinamide (<bold>6b</bold>), 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 <bold>6b</bold> was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D<sub>2</sub> and 5‐HT<sub>1A</sub> receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0–7) of EAE. Compound <bold>6b</bold> reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL‐6, IL‐1, and GM‐CSF, T<sub>H</sub>1 cytokine IFN‐γ, T<sub>H</sub>17 cytokine IL‐17, as well as the signature transcription factors of T<sub>H</sub>1 (T‐bet) and T<sub>H</sub>17 (RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti‐apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The <italic>in vitro</italic> treatment with <bold>6b</bold> protected oligodendrocyte cell line OLN‐93 and neuronal cell line PC12 from mitogen‐activated normal T cells or myelin basic protein‐activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation.</p> </sec> <sec id="jnc13198-sec-1002" sec-type="section"> <p> <boxed-text content-type="graphic" id="jnc13198-blkfxd-0002" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgj2xsv0bs4" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune‐mediated damage. These data indicate potential usefulness of arylpiperazine‐based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis. </p> </sec> </abstract>