Neuroprotection by tosyl-polyamine derivatives through the inhibition of ionotropic glutamate receptors.
Tosyl-polyamine derivatives such as N-{4-[4-(guanidinobutylamino)-butylamino]butyl}-4-methylbenzenesulfonamide trihydrochroride (TsHSPMG) have been found to strongly inhibit macroscopic currents through heteromeric N-methyl-D-aspartate (NMDA) receptors (NR1/NR2A, NR1/NR2B) and Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (homomeric glutamate receptor 1) receptors expressed in Xenopus laevis oocytes on voltage-clamp recording. In the present study, it was found that the inhibition of NMDA receptor activity induced by tosyl-polyamine derivatives was voltage-dependent. Some mutations located in the intracellular region of the channel pore, such as NR1 E621Q and NR2B W607L, reduced the inhibition by tosyl-polyamine derivatives, suggesting that tosyl-polyamine derivatives penetrate deeply into the channel pore of NMDA receptors. The neuroprotective effects of tosyl-polyamine derivatives against cell injury caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 1 microM TsHSPMG to medium ablated the neurotoxicity induced by NMDA, and a similar effect was observed with 30 microM memantine. The neuroprotective effects of tosyl-polyamine derivatives on NMDA-induced seizures in mice were also assayed. Intracerebroventricular or intravenous injection of TsHSPMG (0.1 or 0.5 mg/kg) decreased the seizures induced by intraperitoneal injection of NMDA in mice. These findings indicate that tosyl-polyamine derivatives exhibit neuroprotective effects not only in primary cultured neurons but also in mice.
Masuko
Takashi
T
College of Pharmacy, Nihon University, Funabashi, Chiba, Japan. kusama.tadashi@nihon-u.ac.jp
Namiki
Rie
R
Nemoto
Yuta
Y
Miyake
Muneharu
M
Kizawa
Yasuo
Y
Suzuki
Toyofumi
T
Kashiwagi
Keiko
K
Igarashi
Kazuei
K
Kusama
Tadashi
T
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003619:Dansyl Compounds / Q000494:pharmacology; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology*; D014982:Xenopus laevis
D000880:Anthraquinones; D003619:Dansyl Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C105932:N(1)-dansylspermine; D018696:Neuroprotective Agents; D011073:Polyamines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014105:Tosyl Compounds; D013096:Spermine; D016202:N-Methylaspartate