Neuroinflammation and Lipoxygenase Pathways in Neurodegenerative Disorders

Neuroinflammation is a hallmark of many neurodegenerative disorders including Alzheimer’s, Parkinson’s and multiple sclerosis. Activated microglia and astrocytes release proinflammatory cytokines, chemokines and reactive oxygen species, amplifying neuronal injury. Among lipid mediators, lipoxygenase (LOX) enzymes oxidise polyunsaturated fatty acids to generate leukotrienes, lipoxins and other eicosanoids that modulate vascular permeability, glial recruitment and synaptic function. Isoforms such as 5-LOX and 12/15-LOX are upregulated in disease states, contributing to amyloid precursor protein processing, tau hyperphosphorylation, blood–brain barrier disruption and neuronal death. Crosstalk between LOX pathways, cytosolic phospholipase A2 and NF-κB potentiates chronic inflammation. Emerging evidence links LOX-derived mediators to impaired neurogenesis, synaptic loss and cognitive decline. Pharmacological inhibition of LOX activity or antagonism of leukotriene receptors shows promise in attenuating neuroinflammatory responses and restoring brain function.

Research from Nature Portfolio

Recent studies have demonstrated that antagonism of leukotriene receptors by the anti-asthmatic drug montelukast reduces neuroinflammation, enhances hippocampal neurogenesis and improves learning and memory in aged rodents through inhibition of the GPR17 receptor. Another investigation revealed that inflammatory eicosanoids—thromboxane A2, prostaglandin E2 and leukotriene D4—engage Gαq-coupled neuronal receptors to upregulate amyloid precursor protein expression, while blockade of eicosanoid synthesis lowers brain APP levels in a transgenic model of amyloid pathology. These findings underscore the capacity of lipoxygenase-derived mediators to modulate key disease processes and highlight eicosanoid signalling as a viable therapeutic target in neurodegeneration.

Neuroinflammation and Lipoxygenase Pathways in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in neuroinflammation and lipoxygenase pathways in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Neuroinflammation: Activation of the brain’s innate immune response characterised by glial activation and release of proinflammatory mediators.

5-Lipoxygenase (5-LOX): Enzyme that catalyses the oxygenation of arachidonic acid to generate leukotrienes, potent inflammatory lipid mediators.

Leukotrienes: Bioactive lipids produced by lipoxygenase activity that regulate vascular permeability, chemotaxis and neuronal signalling.

Gαq-coupled receptors: A class of G-protein coupled receptors that activate phospholipase C upon ligand binding, modulating calcium-dependent pathways.

Neurogenesis: The process by which new neurons are generated from neural stem cells, contributing to cognitive function and brain repair.

References

1. Leukotriene signaling as molecular correlate for cognitive heterogeneity in aging: an exploratory study. Frontiers in Aging Neuroscience (2023).
2. Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases. Mediators of Inflammation (2017).
3. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nature Communications (2015).
4. The Lipoxygenases: Their Regulation and Implication in Alzheimer’s Disease. Neurochemical Research (2015).
5. Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. Journal of Neuroinflammation (2015).
6. The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease phenotype. Frontiers in Cellular Neuroscience (2015).
7. Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia. Journal of Neuroinflammation (2006).
8. Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer’s Disease with Plaques and Tangles. PLOS ONE (2013).
9. Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors. Scientific Reports (2015).