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The low affinity neurotensin receptor antagonist levocabastine impairs brain nitric oxide synthesis and mitochondrial function by independent mechanisms
Author(s) -
LoresArnaiz Silvia,
Karadayian Analía G.,
Gutnisky Alicia,
Rodríguez de Lores Arnaiz Georgina
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14232
Subject(s) - neurotensin , nitric oxide synthase , chemistry , antagonist , endocrinology , pharmacology , nitric oxide , medicine , mitochondrion , receptor , synaptosome , mitochondrial respiratory chain , receptor antagonist , neuropeptide , biology , biochemistry , in vitro
Neurotensin is known to inhibit neuronal Na + , K + ‐ ATP ase, an effect that is rescued by nitric oxide ( NO ) synthase inhibition. However, whether the neurotensinergic and the nitrergic systems are independent pathways, or are mechanistically linked, remains unknown. Here, we addressed this issue and found that the administration of low affinity neurotensin receptor ( NTS 2) antagonist, levocabastine (50 μg/kg, i.p.) inhibited NO synthase ( NOS ) activity by 74 and 42% after 18 h in synaptosomal and mitochondrial fractions isolated from the Wistar rat cerebral cortex, respectively; these effects disappeared 36 h after levocabastine treatment. Intriguingly, whereas neuronal NOS protein abundance decreased (by 56%) in synaptosomes membranes, it was enhanced (by 86%) in mitochondria 18 h after levocabastine administration. Levocabastine enhanced the respiratory rate of synaptosomes in the presence of oligomycin, but it failed to alter the spare respiratory capacity; furthermore, the mitochondrial respiratory chain ( MRC ) complexes I– IV activities were severely diminished by levocabastine administration. The inhibition of NOS and MRC complexes activities were also observed after incubation of synaptosomes and mitochondria with levocabastine (1 μM) in vitro . These data indicate that the NTS 2 antagonist levocabastine regulates NOS expression and activity at the synapse, suggesting an interrelationship between the neurotensinergic and the nitrergic systems. However, the bioenergetics effects of NTS 2 activity inhibition are likely to be independent from the regulation of NO synthesis.