Dopamine D2 and D3 receptor agonists limit oligodendrocyte injury caused by glutamate oxidative stress and oxygen/glucose deprivation

Abstract

Dopamine receptor activation is thought to contribute adversely to several neuropathological disorders, including Parkinson's disease and schizophrenia. In addition, dopamine may have a neuroprotective role: dopamine receptor agonists are reported to protect nerve cells by virtue of their antioxidant properties as well as by receptor-mediated mechanisms. White matter injury can also be a significant factor in neurological disorders. Using real-time RT-PCR, we show that differentiated rat cortical oligodendrocytes express dopamine D2 receptor and D3 receptor mRNA. Oligodendrocytes were vulnerable to oxidative glutamate toxicity and to oxygen/glucose deprivation injury. Agonists for dopamine D2 and D3 receptors provided significant protection of oligodendrocytes against these two forms of injury, and the protective effect was diminished by D2 and D3 antagonists. Levels of oligodendrocyte D2 receptor and D3 receptor protein, as measured by Western blotting, appeared to increase following combined oxygen and glucose deprivation. Our results suggest that dopamine D2 and D3 receptor activation may play an important role in oligodendrocyte protection against oxidative glutamate toxicity and oxygen-glucose deprivation injury.

Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia

“…Other mechanisms are consistent with neurochemicallybased models that suggest increased prefrontal cortex dopaminergic neurotransmission underlies some of the beneficial effects of atypical antipsychotics (Barch and Carter, 2005;Eltayb et al, 2005;Li et al, 2005). Consistent with the possibility that this effect could be mitigated by oligodendrocytes, in vitro models have suggested that dopamine stimulation may be protective of oligodendrocytes (Belachew et al, 1999;Rosin et al, 2005) and/or promote the genesis of new cells (Van Kampen et al, 2004). Finally, recent studies suggest that the Neuregulin 1 gene, one of the genetic loci most strongly linked to schizophrenia (Li et al, 2004;Liu et al, 2005;Stefansson et al, 2003; for review see Tosato et al, 2005), may be particularly important for adequate myelination of smaller diameter axons (Michailov et al, 2004).…”

Mice with Conditional Inactivation of Fibroblast Growth Factor Receptor-2 Signaling in Oligodendrocytes Have Normal Myelin But Display Dramatic Hyperactivity when Combined with Cnp1 Inactivation

“…Although OLs have dopamine receptors (Bongarzone et al, 1998;Howard et al, 1998;Rosin et al, 2005), how modulation of these by Fgfr2 and CNP elimination would lead to hyperactivity is not clear. It is likely that the hyperactive behavior of FFCC mice is related to functional abnormalities in dopaminergic neurons rather than dopamine receptor-mediated alterations in OLs.…”

Variations in oligodendrocyte-related gene expression across multiple cortical regions: implications for the pathophysiology of schizophrenia

“…It is possible that inadequate myelination, whether due to abnormal development, maintenance or oligodendrocyte death, contributes to some of the deficits necessary to impair or alter signal flow and brings about at least some of the symptoms of SZ. In addition to affecting signal conductance and propagation (Baumann and Pham-Dinh, 2001;Waxman and Bangalore, 2004), abnormalities in myelin and oligodendrocytes are well-positioned to account for many of the neurobiological disturbances associated with SZ : oligodendrocytes are involved in regulating glutamate function and are in turn affected by glutamate (Gallo and Ghiani, 2000;Matute et al, 2006;Park et al, 2004) ; oligodendrocyte precursors express dopamine D 2 and D 3 receptors (Bongarzone et al, 1998;Nikulina et al, 1995 ;Rosin et al, 2005) ; down-regulation of oligodendrocyte-associated genes can affect the levels and metabolism of dopamine (Nikulina et al, 1995); as described by Segal et al (2007), abnormalities in oligodendrocyte-associated gene expression in rodent models can influence neuronal morphology with features similar to those described in SZ (Benes et al, 1986;Rajkowska et al, 1998;Selemon et al, 1998); oligodendrocytes provide neurotrophic support (Deng et al, 2004;Du and Dreyfus, 2002) ; finally, there is an apparent temporal relationship between myelination and the onset of SZ (Benes, 1989;Benes et al, 1994;Giedd et al, 1999;Goldman-Rakic and Selemon, 1997;Huttenlocher, 1979 ;Terry et al, 1987). Thus, myelin gene expression abnormalities could have consequences for cytoarchitectural and chemoarchitectural organization that are consistent with some of the most robust neurobiological findings in SZ and with the disconnectivity hypothesis.…”