The low affinity neurotensin receptor antagonist levocabastine impairs brain nitric oxide synthesis and mitochondrial function by independent mechanisms

Abstract

Neurotensin is known to inhibit neuronal Na , K -ATPase, 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 (NTS2) 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 NTS2 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 NTS2 activity inhibition are likely to be independent from the regulation of NO synthesis.

Transcriptome analysis reveals genes associated with stem cell activation by physical exercise in the dentate gyrus of aged p16Ink4a knockout mice

“…This may indicate that the ablation of p16 leads to an inflammatory and dismetabolic state, without evident effect on neurogenesis, as no change is observed in stem and progenitor cells or dentate gyrus neurons ( Micheli et al, 2019 ). Other genes upregulated in Set B are involved in cell signaling, such as Magt1 that activates the Mapk pathway ( Bi et al, 2021 ), and Homer2 , involved in glutamate signaling ( Smothers et al, 2016 ), or genes activated in conditions involving neuroplasticity, namely, Slc16A1 , the most abundant lactate transporter in the central nervous system, involved in activation of cellular brain metabolism and pH control ( Halliday et al, 2019 ); or NTSr2 that regulates NOS expression and activity at the synapse ( Lores-Arnaiz et al, 2017 ); or also Rhoq , which plays an important role in axon elongation ( Koinuma et al, 2021 ).…”