Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS.
Tramiprosate, a small aminosulphonate compound, is present in various species of red marine algae. In this study, we examined whether tramiprosate protects neurons and improves functional recovery following ischemic stroke in rats subjected to the intraluminal filament model of MCAO and further explored the underlying mechanisms. Tramiprosate dose-dependently reduced the infarct volume after MCAO, and the therapeutic time window of tramiprosate (50 mg/kg) for cerebral ischemia was at least 6 h. Moreover, functional assays and histochemical staining were performed. Significant neurological functional recovery was found after tramiprosate (50 mg/kg) administration in all three functional assays performed (modified neurological severity score, foot-fault test and adhesive-removal somatosensory test). Tramiprosate significantly attenuated OGD- or NMDA-induced injury in NGF-differentiated PC12 cells and primary cortical neurons. Furthermore, the neuroprotective effect of tramiprosate was partially blunted by the NMDA receptor (NMDAR) antagonist MK801 both in vitro and in vivo, indicating that tramiprosate might confer neuroprotection against stroke via the NMDAR. Based on co-immunoprecipitation and western blotting, tramiprosate decreased the intensity of the association between nNOS and PSD95, and tramiprosate also inhibited the translocation of nNOS from the cytosol to the membrane without affecting the total nNOS expression level both in vitro and in vivo. In conclusion, tramiprosate dose-dependently provides neuroprotection in vitro and in vivo against ischemic stroke, and the neuroprotective effect of tramiprosate may be partially attributed to disruption of the interaction between PSD95 and nNOS and inhibition of nNOS translocation.
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Shuangchan
S
Wu
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Yuan
Y
Yue
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Hui
H
Tian
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Li
L
Tao
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Yuting
Y
Wang
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Jin
J
Xiang
Department of Pharmacology, Hubei University of Science and Technology, Xianning, China.
Shi
S
Wang
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China. Electronic address: dinghong1106@whu.edu.cn.
Hong
H
Ding
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy*; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; C001355:tramiprosate; D052248:Nitric Oxide Synthase Type I
Functional recovery; Ischemic stroke; PSD95–nNOS; Tramiprosate