COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord

Abstract

Background: While multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are primarily inflammatory and degenerative disorders respectively, there is increasing evidence for shared cellular mechanisms that may affect disease progression, particularly glial responses. Cyclooxygenase 2 (COX-2) inhibition prolongs survival and cannabinoids ameliorate progression of clinical disease in animal models of ALS and MS respectively, but the mechanism is uncertain. Therefore, three key molecules known to be expressed in activated microglial cells/macrophages, COX-2, CB2 and P2X7, which plays a role in inflammatory cascades, were studied in MS and ALS post-mortem human spinal cord.

Physiological and pathological functions of P2X7 receptor in the spinal cord

“…Consistent with this hypothesis an increase in P2X7R immunoreactivity has been observed in activated microglia of two transgenic models of Alzheimer's disease [71,72] in microglia/ macrophages of spinal cord undergoing multiple or amyotrophic lateral sclerosis [73], in ischemic cortical tissue [74], and in a model of kainite-induced seizures [62] suggesting that microglial P2X7R, together with P2X4R, might be a general mediator of stress during pathological states. Besides uptake and release of inflammatory molecules, other pathways might contribute to microglial effects on neuronal excitability and disease outcome.…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…Thus, the levels of anandamide and 2-AG are elevated in the spinal cord of SOD-1 mutant mice [156,160], in parallel to an increase in the expression of N-acyl-phosphatidylethanolamine-selective phospholipase D, the enzyme that synthesizes anandamide, but no changes in diacylglycerol lipase, the enzyme that synthesizes 2-AG, and in FAAH and MAGL, the 2 major degradative enzymes for the 2 major endocannabinoids [161]. In addition, CB 2 R experience an important upregulatory response in the spinal cord of SOD-1 mutant and TDP-43 transgenic mice [158,161,162], as well as in patients with ALS [163]. This upregulation appears to occur predominantly in microglial elements recruited at lesioned sites [162,163], so that it may facilitate the beneficial effects derived from selectively targeting this receptor in the control of microglial toxicity for motor neurons.…”

“…In addition, CB 2 R experience an important upregulatory response in the spinal cord of SOD-1 mutant and TDP-43 transgenic mice [158,161,162], as well as in patients with ALS [163]. This upregulation appears to occur predominantly in microglial elements recruited at lesioned sites [162,163], so that it may facilitate the beneficial effects derived from selectively targeting this receptor in the control of microglial toxicity for motor neurons. However, to determine the changes in CB 1 R remains controversial, with a study reporting downregulatory responses in the spinal cord of SOD-1 mutant mice, even at early presymptomatic phases [164], which may predispose motor neurons to excitotoxic events, given the role that CB 1 R play in the control of glutamate homeostasis.…”

Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

“…P2X7R can modulate the main lipid routes inside the cell (Fig. 1c), which include the phospholipase enzymes [31], arachidonic acid metabolism enzymes [43], and sphingosine-and ceramide-metabolism enzymes [27,45]. Additionally, P2X7R was identified in two different domains in the plasma membrane [27], as discussed in the immune system section below.…”

“…Despite this wide assortment of functions, this review will focus on the ability of P2X7R to modulate lipid pathways through the activation of different enzymes, such as, phospholipase A 2 (PLA2) [27,28], phospholipase C (PLC) [29][30][31], phospholipase D (PLD) [32][33][34][35][36][37][38][39], and sphingomyelinases [27,36]. Additionally, it will discuss how these enzymes modify arachidonic acid and its analogues [40][41][42][43][44] as well as ceramides [27,45,46].…”