Effects of Nitric Oxide on the Survival and Neuritogenesis of Cerebellar Purkinje Neurons

Abstract

Nitric oxide has been investigated widely both during neurodevelopment and in neurological diseases. However, whilst it has been established that nitric oxide-producing enzymes of nitric oxide synthase family are expressed in cerebellar Purkinje neurons, the effects of nitric oxide on the viability and morphology of these neurons remain unknown. Here, we have demonstrated that the activity of neuronal nitric oxide synthase, but not the inducible or endothelial forms of this enzyme, is required to support the survival of a proportion of cerebellar Purkinje neurons in vitro. We discovered that donation of high concentrations of exogenous nitric oxide reduces Purkinje neuron survival in culture and that peroxynitrite is also toxic to these cells. Finally, we demonstrated that exogenous nitric oxide and peroxynitrite reduce both the magnitude and the complexity of the neurite arbour extended by cerebellar Purkinje neurons. Taken together, these findings reveal that whilst a low level of endogenous nitric oxide, released by the activity of neuronal nitric oxide synthase, is beneficial to cerebellar Purkinje neurons in vitro, high levels of exogenous nitric oxide and peroxynitrite are detrimental to both the survival of these neurons and to their ability to extend processes and form functional neural networks.

Nitric Oxide Production in the Striatum and Cerebellum of a Rat Model of Preterm Global Perinatal Asphyxia

“…The Purkinje cell population (which express parvalbumin, but not nNOS) is sensitive to peroxynitrite, but these cells also need a small amount of NO to survive (Oldreive et al 2012). During normal postnatal development, the expression and activity of cerebellar nNOS increases slowly throughout the first week.…”

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects

“…The described disturbances of synthesis and release of nitric oxide were actively studied in the aspect of the hypothesis according to which schizophrenia is conditioned by disturbed neurogenesis. A paper by Oldreive et al ( 2012 ) has shown that an increased level of nNOS and nitric oxide deteriorates the survival rate of Purkinje cells of the cerebellum in vitro (Oldreive et al, 2012 ). We have previously mentioned that the increased activity of nNOS was noticed in Purkinje cells in patients with schizophrenia (Bernstein et al, 2001 ).…”

Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories

“…Furthermore, in addition to the direct effects of NO on cell survival, it has been established that within cells, NO interacts with superoxide to form peroxynitrite. As for high concentrations of NO per se, peroxynitrite has also been shown to be important in triggering neuronal death [35][36][37] . It is known that NO induces neuronal death by either necrotic or apoptotic pathways, both of which have been implicated in neurodegeneration [38] .…”