Nitric Oxide Synthase Mediates the Ability of Darbepoetin Alfa to Improve the Cognitive Performance of STOP Null Mice

Abstract

STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.

L-Arginine Add-On Treatment for Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

“…Ayrıca, şizofreninin değişik yönlerini hedef alan hayvan modellerinde NO sinyal iletiminin değiştiği ortaya konmuştur (Ribeiro ve ark. 2013, Kajitani ve ark. 2010.…”

Nitric Oxide Synthase Mediation of Darbepoetin's Cognitive Benefits: A Paradoxical Effect?

“…Recently, Kajitani et al (2010) reported observations to support that enhanced nitric oxide signaling might be the mechanistic basis for erythropoietin's cognitive benefits in schizophrenia. However, numerous studies have suggested that enhanced nitric oxide signaling might adversely impact schizophrenia.…”

“…However, numerous studies have suggested that enhanced nitric oxide signaling might adversely impact schizophrenia. For example, increased nitric oxide signaling has been demonstrated to underlie the information-processing deficits in the phencyclidine model of schizophrenia (Palsson et al, 2010); intriguingly, the nitric oxide synthase inhibitor (N (G)-nitro-L-arginine methyl ester (L-NAME)) used by the authors in this study (Kajitani et al, 2010) has been reported to ameliorate the phencyclidine-induced cognitive deficits (Klamer et al, 2001). Moreover, treatment with minocycline, a nitric oxide synthase inhibitor, improved cognitive deficits in schizophrenia patients in a double-blind, randomized, placebo-controlled study (Levkovitz et al, 2010).…”

“…Contextually, it is important to note that the beneficial effects of erythropoietin on cognitive deficits in schizophrenia have been demonstrated in patients that were stabilized with antipsychotic treatment; these patients did not have severe positive symptoms (Ehrenreich et al, 2007). If the enhanced nitric oxide signaling is indeed the predominant mechanistic basis for erythropoietin's benefits (Kajitani et al, 2010), then, this is an issue of concern because of the potential of this mechanism to worsen schizophrenia symptomsFperhaps with long-term use.…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…Initial studies showed that MAP6 knockout mice have reduced number of synaptic vesicles and impaired synaptic plasticity (Andrieux et al 2002). Later, it was shown that, in addition to changes in glutamatergic synaptic transmission, these mice also present alterations in dopaminergic, acetylcholinergic, nicotinic, serotonergic, and noradrenergic neurotransmission (Bouvrais-Veret et al 2007, 2008Brun et al 2005;Delotterie et al 2010;Fournet et al 2010Fournet et al , 2012bFradley et al 2005;Kajitani et al 2010;Powell et al 2007). These alterations recapitulate some clinical features observed in schizophrenia disorders (Andrieux et al 2002;Fournet et al 2012b).…”