FTY720 attenuates excitotoxicity and neuroinflammation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2004-

Anti-Inflammatory Agents/*therapeutic use ; Brain Diseases/*chemically induced ; Brain Diseases/*drug therapy ; Excitatory Amino Acid Agonists/*toxicity ; Fingolimod Hydrochloride/*therapeutic use; Animals ; Animals, Newborn ; Anti-Inflammatory Agents/pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Cerebellum/drug effects ; Cerebral Cortex/cytology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Fingolimod Hydrochloride/pharmacology ; In Vitro Techniques ; Kainic Acid/toxicity ; L-Lactate Dehydrogenase (Cytochrome)/metabolism ; Male ; N-Methylaspartate/toxicity ; Neurons/drug effects ; Organ Culture Techniques ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Time Factors

Background: FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1R). However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. In this study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death and examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection.
Methods: Primary neuronal and organotypic cortical cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic cell death (measured by lactate dehydrogenase (LDH) assay or propidium iodide uptake, respectively). The effects of FTY720 treatment (10, 100 and 1,000 nM) on neuronal survival were examined. As an in vivo model of neuronal death and inflammation, we used intracerebroventricular (icv) administration of kainic acid (KA; 0.5 μg/2 μl) in Sprague-Dawley rats. FTY720 was applied icv (1 μg/2 μl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 3 days after icv. Rats were evaluated for neurological score, neuronal loss in CA3 hippocampal region and activation of microglia at the lesion site. In addition, we tested FTY720 as a modulator of microglia responses using microglial cell cultures activated with lipopolysaccharide (LPS) and its effects in stress signalling pathways using western blotting for p38 and JNK1/2 mitogen-activated protein kinases (MAPKs).
Results: FTY720 was able to reduce excitotoxic neuronal death in vitro. Moreover, in vivo repeated FTY720 administration attenuated KA-induced neurodegeneration and microgliosis at the CA3 lesion site. Furthermore, FTY720 negatively modulates p38 MAPK in LPS-activated microglia, whereas it had no effect on JNK1/2 activation.
Conclusions: These data support a role for FTY720 as a neuroprotective agent against excitotoxin-induced neuronal death and as a negative modulator of neuroinflammation by targeting the p38 MAPK stress signalling pathway in microglia.

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0 (Anti-Inflammatory Agents)
0 (Excitatory Amino Acid Agonists)
6384-92-5 (N-Methylaspartate)
EC 1.1.2.3 (L-Lactate Dehydrogenase (Cytochrome))
G926EC510T (Fingolimod Hydrochloride)
SIV03811UC (Kainic Acid)

Date Created: 20150509 Date Completed: 20160808 Latest Revision: 20220410

20250114

PMC4429813

10.1186/s12974-015-0308-6

25953296