Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB₁and CB₂receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB₁and CB₂receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB₁receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB₁receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-α, respectively. CB₁receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB₂receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB₂-positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB₁and CB₂receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

Oligodendrocyte precursor cells (OPCs) originate in specific areas of the developing central nervous system (CNS). Once generated, they migrate towards their destinations where they differentiate into mature oligodendrocytes. In the adult, 5-8% of all cells in the CNS are OPCs, cells that retain the capacity to proliferate, migrate and differentiate into oligodendrocytes. Indeed, these endogenous OPCs react to damage in demyelinating diseases, like multiple sclerosis (MS), representing a key element in spontaneous remyelination. In the present work, we review the specific interactions between OPCs and other glial cells (astrocytes, microglia) during CNS development and in the pathological scenario of MS. We focus on: i) the role of astrocytes in maintaining the homeostasis and spatial distribution of different secreted cues that determine OPC proliferation, migration and differentiation during CNS development; ii) the role of microglia and astrocytes in the redistribution of iron, which is crucial for myelin synthesis during CNS development and for myelin repair in MS; iii) how microglia secrete different molecules, e.g. growth factors, that favor the recruitment of OPCs in acute phases of MS lesions; and iv) how astrocytes modify the extracellular matrix in MS lesions, affecting the ability of OPCs to attempt spontaneous remyelination. Together, these issues demonstrate how both astroglia and microglia influence OPCs in physiological and pathological situations, reinforcing the concept that both development and neural repair are complex and global phenomena. Understanding the molecular and cellular mechanisms that control OPC survival, proliferation, migration and differentiation during development, as well as in the mature CNS, may open new opportunities in the search for reparative therapies in demyelinating diseases like MS.

Multiple sclerosis is a demyelinating disease that affects ∼2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood–brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood–brain barrier.