Trimethyltin intoxication up-regulates nitric oxide synthase in neurons and purinergic ionotropic receptor 2 in astrocytes in the hippocampus.
Nitric oxide (NO) and purinergic ionotropic receptors (P2X) mediate cellular events in the central nervous system (CNS) under physiological conditions as well as during pathological events, and they have been recently proposed to interact in mediating CNS response to injury (Viscomi et al. [2004] Neuroscience 123:393-404; Florenzano et al. [2008] Pflugers Arch. 452:622-644). Trimethyltin (TMT) is an organotin compound that generates neurotoxic effects, and it has been used in a model of neurodegenerative disease and memory dysfunction. TMT causes neuronal death and reactive gliosis primarily in the hippocampus and other limbic regions. In the present study, we examined the degenerative events and the expression of nitric oxide synthase (NOS) and P2X receptor subtypes (P2X(1,2,4,7)Rs) that were induced by TMT administration at different time points (3, 7, 14, and 21 days) by conventional and confocal microscopy and Western blotting. Massive glial activation and neuronal death in the CA1 and CA3 regions were observed after TMT treatment. In these areas, astrocytic P2X(2)R and neuronal NOS were temporarily enhanced in association with the progression of neuronal death. In the hippocampus, the physiological expression of P2X(1)R, P2X(4)R, and P2X(7)R was not modified by TMT. The present data demonstrate that, as in other neurodegenerative models, TMT-induced hippocampal degeneration is associated with nitrergic and purinergic activations. Nevertheless, at odds with previous data, in this model the two systems are active in segregated cell populations, namely, P2XR in astrocytes and NOS in neurons. Finally, the temporal relations between P2XR and NOS expression and neuronal degeneration suggest interactions between P2XR/NO signaling and cell survival.
Latini
Laura
L
Santa Lucia Foundation IRCCS, Rome, Italy.
Geloso
Maria Concetta
MC
Corvino
Valentina
V
Giannetti
Stefano
S
Florenzano
Fulvio
F
Viscomi
Maria Teresa
MT
Michetti
Fabrizio
F
Molinari
Marco
M
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002491:Central Nervous System Agents / Q000633:toxicity*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058469:Receptors, Purinergic P2X; D013997:Time Factors; D014298:Trimethyltin Compounds / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
D002491:Central Nervous System Agents; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D014298:Trimethyltin Compounds; C046488:trimethyltin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I