Pleotropic Roles of Autotaxin in the Nervous System Present Opportunities for the Development of Novel Therapeutics for Neurological Diseases.
Deron R HerrWee Siong ChewR L SatishWei-Yi OngPublished in: Molecular neurobiology (2019)
Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.
Keyphrases
- brain injury
- major depressive disorder
- clinical trial
- high glucose
- diabetic rats
- cerebrospinal fluid
- traumatic brain injury
- multiple sclerosis
- oxidative stress
- subarachnoid hemorrhage
- stress induced
- neuropathic pain
- drug induced
- metabolic syndrome
- phase iii
- blood brain barrier
- cerebral ischemia
- bipolar disorder
- peripheral nerve
- spinal cord injury
- type diabetes
- small molecule
- single cell
- open label
- white matter
- mesenchymal stem cells
- stem cells
- hepatitis c virus
- hiv infected
- mental health
- human immunodeficiency virus
- resting state
- endothelial cells
- emergency department
- adipose tissue
- functional connectivity
- cell therapy
- cancer therapy
- signaling pathway
- hiv positive
- men who have sex with men
- uric acid
- hiv aids
- optical coherence tomography
- skeletal muscle
- hiv testing
- severe traumatic brain injury
- age related macular degeneration
- cognitive decline
- alcohol consumption
- heat stress
- cataract surgery