Trimethyltin intoxication up‐regulates nitric oxide synthase in neurons and purinergic ionotropic receptor 2 in astrocytes in the hippocampus

Abstract

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.

Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT) Administration

“…Neuronal death shows a delayed onset (two days after treatment) and progressively worsens: it develops over three weeks [7,8,17], probably on account of the high affinity of rat hemoglobin for TMT [17,29], involving CA3 earlier and more severely than CA1 [12,64]. …”

The Neurogenic Effects of Exogenous Neuropeptide Y: Early Molecular Events and Long-Lasting Effects in the Hippocampus of Trimethyltin-Treated Rats

“…Rats exposed to TMT show severe loss of pyramidal neurons in the CA3/hilus and CA1 hippocampal subfields, with selective sparing of GABAergic interneurons expressing parvalbumin and calretinin [17], [18], [21]–[24]. Neuronal damage shows a subacute pattern developing over three weeks [25] and is associated with astroglial and microglial activation [26]–[29], enhanced neurogenesis [30], seizures and cognitive impairment [17], [18]. While the mechanisms by which TMT induces neurodegeneration are still not conclusively clarified, many hypotheses suggest that neuronal damage could be largely dependent on calcium overload, possibly as a consequence of its release from intracellular stores [24], [31], [32].…”

Pathophysiology of astroglial purinergic signalling

“…TMT causes astrogliosis and neuronal death in the hippocampus and other limbic regions [185]. These authors examined the expression of nitric oxide synthase (NOS) and P2XRs (P2X 1,2,4,7 ) that were induced by TMT administration at different time points.…”

“…The presence of the Ca 2+ -dependent NO synthase (NOS) isoforms in astrocytes makes it conceivable that similarly to neurones, P2XR-mediated rises in Ca 2+ may directly trigger NO production. Indeed, in purified cortical astrocytes in culture, ] i elevation [184,185]. Astroglial P2Y 2 Rs are coupled to α v β 3 /β 5 integrin signalling pathways, which control cytoskeletal remodelling and motility [172].…”