Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

Abstract

Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer's and Parkinson's diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression.

Figure 1

CysLTs in neurodegenerative diseases. The circle shows the changes of the CysLT pathway components grouped for the different neurodegenerative diseases and observed in human patients and in in vitro/in vivo models.

Figure 2

Spatio-temporal expression of the CysLT1 and CysLT2 receptors after focal cerebral ischemia in rodents. (a) In the control brain, CysLT1 receptor is weakly expressed (time 0) [15, 61]. Following middle cerebral artery occlusion (MCAo), its expression, at the ischemic core level, is biphasic: at day 1 postischemia, the receptor is mainly expressed in neurons (red wave) [15, 60, 61] and, to a lesser extent, in astrocytes (orange) [15]; between 7 and 14 days postischemia, it increases in microglia (blue) [15]. In the boundary zone, that is, the “penumbra,” the receptor's expression is mainly expressed in neurons (red wave) at 3 days [60] and then it increases over time in most hypertrophic astrocytes (yellow) [15] and microvascular endothelial cells (brown) [15], reaching a peak after 14 days. (b) In the healthy brain, the CysLT2 receptor is primarily expressed in GFAP⁺ astrocytes around the lateral ventricles and in the cortex [18]. In the ischemic core, one day postischemia, the expression of CysLT2 receptor shows a rapid and transient peak in neurons (red) [18, 60] and then gradually disappeared over 3 days. In the hypertrophic microglia (blue), it slowly increases over time and reaches a peak after 14 days [18]. In the penumbra (boundary zone), following its induction at day 0, the receptor's expression is mainly expressed in neurons (red wave) at 3 days [60] and then it increases over time in astrocytes [18]. After one week, its expression also increases in the microglia [18].