7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

Abstract

a b s t r a c tNeuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS þ and Phospho-Thr34-DARPP-32 þ cells, accompanied by a consequent decrease of total DARPP-32 þ cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.

The rat striatum responds to nigro-striatal degeneration via the increased expression of proteins associated with growth and regeneration of neuronal circuitry

“…These alterations in the proteome might be expected when considering that as destruction of afferent SNc dopamine neurons proceeds, there is a concomitant loss of proteins related to dopaminergic connectivity (i.e., synapses) within the striatum. Such findings support previous assertions that nigro-striatal denervation negatively affects DARPP-32 expression [24], though this contrasts with other (indirect) estimations suggesting that denervation may not affect striatal DARPP-32 levels [25]. It will be important to clarify the effect of dopamine denervation on DARPP-32 expression in the striatum of human PD sufferers, as inactivation of DARPP-32 in mice can significantly reduce the possibility of l-dopa induced dyskinesias [26].…”

Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System

“…These mismatches have also been reported in the dorsal and central nuclei of ventral telencephalon of zebrafish [Robra and Thirumalai, 2016], in the lateroventral septum, cerebellum and reticular formation of amphibians , the septal region, the superficial part of the medial cortex, pretectum and rhombencephalic ventromedial tegmentum of reptiles [Smeets et al, 2001[Smeets et al, , 2003, and in the neocortex and cerebellum of mammals [Ouimet et al, 1984[Ouimet et al, , 1992. These data support that DARPP-32 may not only be regulated by dopamine, but also by glutamate, serotonin, noradrenalin, nitric oxide, or somatostatin Svenningsson et al, 2002;Andersson et al, 2005;Nishi et al, 2005;Hara et al, 2010;Rajput et al, 2012;Yuste et al, 2012].…”

Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model

“…It suggests that without affecting the expression of DARPP32 (Fig. 6), AMI potentiated the dopamine signaling pathway by increasing the activation of DARPP32 (45,46). We also found that the marker of de novo neuron synthesis, doublecortin (DCX), was significantly elevated by AMI (Fig.…”