Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity

Abstract

Purpose Our study aimed to elucidate the intracellular processes associated with quinolinic acid (QA)-induced brain injury by acquiring semiquantitative fluorescent images of reactive oxygen species (ROS) generation and positron emission tomography (PET) images of mitochondrial complex I (MC-I) activity. Methods Ex vivo fluorescent imaging with dihydroethidium (DHE) and PET scans with 18F-BCPP-EF were conducted at 3 h and 24 h after QA injection into the rat striatum. Immunohistochemical studies were performed 24 h after QA injection into the rat brain using monoclonal antibodies against neuronal nuclei (NeuN) and CD11b. Results A strong DHE-derived fluorescent signal was detected in a focal area within the QA-injected striatum 3 h after QA injection, and increased fluorescent signal spread throughout the striatum and parts of the cerebral cortex after 24 h. By contrast, 18F-BCPP-EF uptake in the QA-injected rat brain was unchanged after 3 h and markedly decreased after 24 h, not only in the striatum but also in the cerebral hemisphere. The fluorescent signal in the striatum 24 h after QA injection colocalised with microglial marker expression. Conclusions We successfully obtained functional images of focal ROS generation during the early period of excitotoxic injury, and microglial ROS generation and mitochondrial dysfunction were observed during the progression of the inflammatory response. Both ex vivo DHE imaging and in vivo 18F-BCPP-EF-PET were sufficiently sensitive to detect the respective processes of QA-induced brain damage. Our study contributes to the functional imaging of multiple events during the pathological process.

Pharmacological Characterization of [18F]-FNM and Evaluation of NMDA Receptors Activation in a Rat Brain Injury Model

“…For example, the hippocampus could be an interesting target for further studies, due to the dysfunction of NMDARs found in this area in various pathologies such as schizophrenia [ 45 ] or Alzheimer’s disease [ 46 ]. According to the literature, QA has no influence on the bioavailability of opioid receptors [ 28 , 47 , 48 ], therefore, even if FNM can bind to it with a low affinity, the uptake is indeed due to an opening of the NMDARs. Moreover, the z-score analysis and comparison of SUVRs in the NaCl injection area between controls and injured rats shows that saline stereotaxic injection does not cause NMDAR opening.…”

Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature

“…Concomitantly, QA showed pro-oxidative stress activity due to its ability to generate ROS formation. Recently, a study by Hosoi and colleagues (2021) demonstrated that intrastriatal administration of QA in rats induces acute microglia oxidative damage and mitochondrial dysfunction which indicates an acute neurotoxicity effect of QA on the brain via oxidative stress [ 107 ]. The study obtained a functional image of acute oxidative damage in the brain that occurred 3 to 24 h after QA injection.…”

Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process

“…QA toxicity induces mitochondrial alterations while increasing the formation of the reactive oxygen and nitrogen species [ 15 ]. As a result, QA has been previously shown to induce brain damage through mitochondrial damage [ 16 ]. Several studies revealed that QA causes alteration in mitochondrial structure and functions, such as dilatation of cristae, impaired oxygen consumption rate, increased production of reactive oxygen species (ROS), decreased mitochondrial membrane potential (MMP), and impaired oxidative phosphorylation [ 17 – 20 ].…”