Research progress of quinolinic acid in neuropsychiatric diseases

Xiao-Yu Guo, Yan-Qing Han, Wei Lv

1.Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi, China 2.Shanxi Cardiovascular Hospital, Shanxi Medical University, Taiyuan 030000, Shanxi, China

Keywords:Quinolinic acid Ynurenine metabolic pathway Eurodegenerative disease

ABSTRACT Quinolinic acid is a neurotoxic substance produced by tryptophan through the kynurenine metabolism pathway. Quinolinic acid is involved in the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, encephalitis, depression, and schizophrenia. The above process is realized through pathophysiological processes such as excitatory neurotoxicity, metabolic damage, free radical generation and oxidative stress, participation in inflammatory response, induction of neuron and astrocytic apoptosis. This article will explain the metabolic regulation, biological characteristics, and neurotoxicity of quinolinic acid. The research progress of quinolinic acid in Alzheimer's disease, Parkinson's disease, Huntington's disease, depression and subacute sclerosing panencephalitis is also described.

L. Henderson first systematically described Quinolinic acid (QUIN) in the Journal of Biochemistry in 1949[1]. QUIN is also known as 2,3-pyridinedicarboxylic acid[2], Under physiological conditions, QUIN exists in nanomolar concentration and is used by cells as a substrate to synthesize the necessary cofactor nicotinamide adenine dinucleotide; under pathological conditions, tryptophan passes through the kynurenine metabolic pathway It is transformed into QUIN. QUIN produces a series of neurotoxic effects by binding to N-methyl-D aspartate (NMDA) body[1].

1. QUIN is metabolized by the kynurenine pathway

The initial and rate-limiting steps of the kynurenine pathway (Kynurenine pathway, KP) are: tryptophan generates N-formylcanine urine(NFK) under the action of indoleamine-2,3-dioxygenase 1 (IDO1),IDO2 and tryptophan-2,3-dioxygenase(TDO) [3] . NFK produces kynurenine (KYN) under the action of kynurenine formamide. KYN has three metabolic pathways: (1) Kynuric acid (KYNA) is produced under the action of kynurenine aminotransferase, and KYNA is N-methyl-D-aspartate (NMDA) and α by antagonism -7 Nicotinic acetylcholine (α7nACh) receptor to exert neuroprotective effect; (2) KYN produces 3-hydroxyanthranilic acid (3-3-HK) in canine urine ammonia-3-monooxygenase (KMO) , 3-HK generates quinolinic acid (QUIN) through a series of reactions, which activates NMDA receptors to produce neurotoxicity; (3) KYN generates anthranilic acid (AA) through the action of kynureninase (KYNU) AA can play a role in generating QUIN through a series of biochemical reactions[4].

Many studies have found that only monocyte lineage cells have the ability to produce QUIN. Neurons, astrocytes and endothelial cells in the brain may take up and catabolize QUIN[5]. In the nervous system, microglia can also degrade QUIN[6]. Based on the abovementioned QUIN outcome process, two strategies for limiting QUIN neurotoxicity are proposed: (1) neutralizing the role of QUIN by using anti-QUIN monoclonal antibodies, and (2) directly inhibiting activated mononuclear cells using specific KP enzyme inhibitors Cells produce quinolinic acid[5].

2. The neurotoxic effects of QUIN

QUIN is a weakly selective and competitive NMDA receptor agonist. By activating NMDA receptors in neurons, QUIN exerts neurotoxic effects, and QUIN preferentially acts on NR2A and NR2B receptor subunits[2]. The hippocampus and striatum are the areas of the brain most sensitive to QUIN neurotoxicity[6].

The mechanism of QUIN's neurotoxicity is mainly reflected in: (1) QUIN can directly interact with free iron ions to form toxic complexes, exacerbate the formation of ROS, oxidative stress and excitotoxicity, and endogenous iron also directly affects QUIN and NMDA receptor binding[7, 8]. (2) QUIN can cause excitatory poisoning by binding NMDA receptors, increasing cytosolic calcium concentration, consuming ATP and forming free radicals[2]. (3) Inducing lipid peroxidation, producing ROS, increasing iNOS expression, reducing SOD activity and causing mitochondrial dysfunction. (4) Causes excessive phosphorylation of intermediate filaments, leading to unstable cytoskeleton. (5) Quinolinic acid can also promote the release of glutamic acid and inhibit the reuptake of glutamic acid: QUIN is an upstream activator of glutamate receptor, which in turn activates the kinase / phosphatase signaling cascade, and the signal cascade The homeostasis of the phosphorylation system associated with astrocytes and neuronal intermediate silk proteins is disrupted[9, 10]. (6) Quinolinic acid increases phosphorylation of several proteins, including the tau silk protein associated with Alzheimer's disease[4]. (7) Injecting QUIN compound into striatum can cause axonal neuron disease[11]. (8) QUIN destroys the integrity of the blood-brain barrier[12].

QUIN can activate microglia and up-regulate tumor necrosis factor α (TNFα) through the NF-κB pathway, and IFN-α can increase the activity of IDO, which in turn increases the expression of QUIN, that is, QUIN and TNFα promote the production of each other; in addition, QUIN can amplify the inflammatory response by upregulating the expression of several chemokine receptors in human fetal astrocytes, and this is induced by TNFα or interferon The chemokine receptor is comparable[6].

Although QUIN is an agonist of the NMDA receptor, various subtypes and combinations of subunits of the NMDA receptor have different sensitivities to metabolites. QUIN has relatively high selectivity for NMDA receptors in the neocortex and hippocampus, and its activity in the cerebellum and spinal cord is much weaker, probably because the NR2C and NR2B subunits of the NMDA receptor are underexpressed in the cerebellum. At the cellular level, micromolar concentration of QUIN can be cytotoxic to most types of brain cells in vitro and induce the death of rat oligodendrocytes[11]. Similar toxic effects were also observed in primary human astrocytes. This effect can be eliminated by using antagonists of the NMDA receptor, such as memantine, which is also one of the ways to reduce the toxic effects of QUIN[5].

Proinflammatory mediators (such as TNFα) can promote the production of QUIN, interleukin 1β can enhance the excitotoxicity of QUIN[13], and inflammation inhibitors (such as interleukin 4) can reduce the new synthesis of QUIN by inhibiting the active IDO of upstream IDO. Many indole-derived compounds and structurerelated agents can inhibit the production of quinolinic acid by inhibiting the activity of TDO.

3. QUIN and Alzheimer's disease and cognitive impairment

At present, 47 million people worldwide suffer from dementia, which is estimated to increase to about 131 million by 2050. Alzheimer's disease (AD) is a common type of dementia. AD is a neurodegenerative disease whose pathogenesis is due to the accumulation of amyloid β (Aβ) plaques in the human cerebral cortex and peripheral regions and intracellular neurofibrils composed of highly phosphorylated τ protein Tangle, α-synuclein degeneration is also one of the characteristic pathological changes of AD. The main clinical manifestations of AD are impairment of cognitive domain such as memory loss[14].

From preclinical studies to clinical studies of AD, QUIN has been found to be closely related to the pathogenesis of AD. Inoculation of QUIN in the striatum of mice results in increased levels of phosphorylated α-synuclein[15]. QUIN may play a role in AD pathology by promoting tau phosphorylation[16]; QUIN can accelerate Tau amyloid in vitro protein oligomerization[17]. In vitro experiments found that QUIN can cooperate with homocysteine in the early stage of AD, and can trigger ROS generation, lipid peroxidation, Na +, K decrease + -ATPase activity and morphological changes, and eventually cause neurons due to death of necrotic cells Reduced vitality[18]. Autopsy revealed co-localization of TDO and QUIN in hippocampal slices with neurofibrillary tangles and β-amyloid deposition in the elderly[19]. Increased expression of the neurotoxic agent QUIN in peripheral blood mononuclear cells from AD patients, these cells may enter the brain and cause excitotoxicity[20]. The study also found a negative correlation between the level of QUIN and the inverse of the MMSE score in AD patients[21].

Resting state functional magnetic resonance studies have shown that injecting QUIN into the brains of mice induces memory deficits and reduced cortical connectivity and reduced hippocampal plasticity[22].

After inhibiting TDO in the AD fruit fly animal model, QUIN synthesis increased, and the behavioral status of the model was improved[23], which is not consistent with the above-mentioned pathogenesis of QUIN and AD.

4. QUIN and Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by tremor and bradykinesia. The main pathological changes are the death of dopaminergic neurons in the substantia nigra and the presence of eosinophils in the cytoplasm of residual neurons. Inclusion bodies, important components of inclusion bodies include alpha-synuclein. Studies have found that excessive production of QUIN induces α-synuclein aggregation, which leads to neuronal toxicity and PD induction [15]. More QUIN was also detected in patients with Parkinson's disease than in the normal control group. The effects of QUIN can be antagonized by NMNA receptor antagonists, while NMDA antagonists can relieve PD symptoms in vivo and in vitro and exert neuroprotective effects on PD.

5. QUIN and Huntington's disease

Huntington's disease (HD) is a basal ganglia and cerebral cortical degeneration disease characterized by occult onset, slowmoving dance syndromes, mental abnormalities, and dementia. Its pathogenesis is related to neuronal oxidative stress and cortical cortex excitement Sexual poisoning. QUIN-induced striatal lesions are often used to prepare HD animal models. As a free radical scavenger, edaravone can reduce tissue damage and reduce granulocyte production in QUIN-induced HD rat models[24]. Venlafaxine and sertraline can reduce the toxic effects of QUIN on the striatum[25].

6. QUIN and amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late fatal neurodegenerative disease affecting motor neurons, with an incidence of about 1 / 100,000. Most cases of ALS are sporadic, but 5-10% of cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of the cortical and spinal motor neurons. The most common symptoms of ALS are muscle weakness, convulsions, and cramps, which can eventually lead to muscle damage, the disease progresses to later stages, and patients experience symptoms such as difficulty breathing and difficulty swallowing. Studies have found that the possible pathogenesis of ALS includes mutations in the antioxidant enzyme superoxide dismutase 1 gene, increased glutamate excitotoxicity, mitochondrial structure and dysfunction, and free radical-mediated oxidative stress[26] QUIN-based endogenous neurotoxicity has many overlaps in the pathogenesis of ALS. Vanessa X Tan et al. Found that QUIN can be used as a biomarker for ALS[27] Jong-Min Lee et al. also systematically explained the involvement of QUIN in the pathogenesis of ALS [28]. Studies have found that Wedelolactone and gallic acid can alleviate QUIN-induced toxic events and may be effective in preventing and leading to the development of multiple cascades that lead to sALS [26]

7. Quinolinic acid and depression

Depression is a common neuropsychiatric disorder, and recent research suggests that increased inflammation and oxidative stress may play an important role in the pathophysiology of depression. Increased levels of pro-inflammatory factors, IDO will be activated, increase the synthesis of QUIN, and then activate the NMDA receptors in the central nervous system, and stimulate the secretion of interleukin-6 and -1β, thereby promoting the hyperactivity of the hypothalamic pituitary axis, And enhance the deviation of tryptophan metabolism to the production of quinolinic acid and the innate immune interleukin, thereby reducing the synthesis of serotonin and consolidating the depression process[29]. QUIN can affect the synthesis of antioxidant enzymes to increase the effect of oxidative stress[30]. Increased expression of QUIN in microglia in the anterior cingulate gyrus was found in depression models. QUIN can also be used as a biomarker for the effect of ketamine on depression[31, 32].

8. Quinolinic acid and subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a disease caused by progressive brain persistent mutations of measles virus. Children with SSPE may show mild memory decline, resulting in unsatisfactory academic performance and may also show repeated falls. Adult patients can realise reduced memory, altered personality and behavior, impaired gait, and less speech, and may have autonomic nervous system disorders such as fever and sweating in the later stages of the disease [33] Hirofumi Inoue et al. found that the cerebrospinal fluid QA content of patients with SSPE increased compared with the control group, indicating that QA can be used as a biomarker for SSPE[34].

9. QUIN and other neurological diseases

QUIN is also related to learning and memory abilities. Studies have found that QUIN can affect the learning ability of mice and damage hippocampal and synaptic functions[22]. After intracerebroventricular injection of quinolinic acid, the spatial learning and memory abilities of rats were impaired [35]. QUIN expression is increased in patients with traumatic brain injury, and the level of QUIN is correlated with prognosis[36].

10. Summary

QUIN mainly produces neurotoxic effects by binding to NMDA receptors and participates in the pathophysiology of neuropsychiatric diseases such as AD, PD, HD, depression. Further research on the biomarkers of QUIN in the neuropsychiatric diseases mentioned above, and the inhibition of QUIN upstream Enzymes and drugs that inhibit NMDA receptors can be used as therapeutic targets for diseases.