User:Mannintg/Quinolinic Acid

Wikipedia Proposal: Quinolinic Acid

TJ Manning, Trevor Doherty, Jackie Figueredo

Intoduction
Quinolinic acid (QUIN) is a part of the kyurenine pathway. It has been demonstrated that QUIN is involved in several major neurological diseases. Treatment of these diseases could be linked to the regulation of QUIN levels.

History
In 1949 L. Henderson was one of the earliest to describe QUIN. Later, Lapin induced convulsions in mice by injecting the brain ventricle with QUIN. It was not until 1981 that Stone and Perkins showed that QUIN could selectively activate the N-methyl-d-aspartate receptor. Schwarcz later demonstrated that this led to axonal neurodegeneration.

Kynurenine Pathway
The kynurenine pathway accounts for greater than 90% of tryptophan metabolism in the body and acts as a source of NAD+ which the cell requires for normal functioning. Quinolinic acid is a derivative of this pathway and is typically produced by the microglial cells. This section will give a short overview of the pathway which results in the production of quinolinic acid as well as what sort of bodily stimuli (and hormones) result in an increased amount of quinolinic acid.

Normal Function in Central Nervous System
Quinolinic acid is shown to increase the production of NAD+ and have beneficial effects when present in normal physiological concentrations. Furthermore there is evidence that quinolinic acid concentrations in the brain vary according to region and function. This section will investigate the importance of quinolinic acid in normally functioning neurophysiology.

Toxicity
This section on toxicity will delve into QUIN and its behavior as an endogenous excitotoxin. Evidence regarding the various ways in which QUIN leads to neurotoxicity will be fully discussed, including but not limiting to: it's role as an NMDA agonist, effects on glutamate release and inhibition, lipid peroxidation, disruption of the blood-brain barrier, and its ability to induce phosphorylation of cellular structural proteins leading to cytoskeleton destabilization.

Clinical Significance
We will use this section to discuss the many disorders that QUIN is associated with.

Huntington's Disease
Rodent studies have shown that injection or infusion of QUIN into the straitum leads to a similar phenotype of Huntington’s disease patients. This procedure is called the quinolinic acid striatal lesion model or QA lesion model and is often used in transplantation studies. We will focus on the impact of these studies.

Alzheimer’s Disease
Neurotoxic products of QUIN have been found in the cerebral spinal fluid and plasma of patients with Alzheimer’s disease. We will discuss the origins and the affects of these neurotoxic products.

HIV Associated Cognitive Disorders
QUIN may play a role in the pathogenesis of human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND). Characterized by cognitive impairment and dementia, HAND is found in 20% of HIV patients. It has been shown that QUIN is dysregulated in HIV patients. This will further be explained.

Psychiatric Disorders
QUIN may be involved in adolescent melancholic depression, major depression, and bipolar depression. In addition, there is evidence that QUIN plays a role in schizophrenia. We will focus on how these are linked.

Epilepsy, Ischemia, Multiple sclerosis, Migraines, and Parkinson’s Disease
There is evidence that QUIN plays a role in these disorders. We will explore these in more depth.

Treatment Focus
This section will discuss the current research focused on the reduction of QUIN formation which could lead to potential therapies for macrophage/microglial-mediated neurological inflammatory disorders. These treatments are focusing on NMDA antagonists and compounds targeting QUIN synthesis and/or toxicity which have shown protection of neurons against QUIN excitotoxicity.

Division of Workload
We have agreed to read the relevant literature by September 27th. We will then discuss the topics outlined in this proposal and split up the responsibilities for the topics. Each week we will have meetings to update each other on our progress and to discuss any difficulties.