Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia.

Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6).

Cannabinoids and neuroprotection in CNS inflammatory disease.

The current failure of potent immunosuppressive agents to control progressive disease in multiple sclerosis has moved a focus from immunotherapy towards the need for neuroprotection. There is increasing evidence for cannabinoid-mediated control of symptoms, which is being more supported by the underlying biology. However there is accumulating evidence in vitro and in vivo to support the hypothesis that the cannabinoid system can limit the neurodegenerative possesses that drive progressive disease, and may provide a new avenue for disease control.

Cannabinoid-mediated neuroprotection following interferon-gamma treatment in a three-dimensional mouse brain aggregate cell culture.

Multiple sclerosis is increasingly recognized as a neurodegenerative disease which is triggered by inflammation in the central nervous system (CNS). Demyelination-associated axonal or neuronal damage is a primary cause of disability and has thus far not been successfully targeted by available drug therapies. The neuroprotective properties of both endogenous and administered cannabinoids have been shown in in vivo and in vitro models of CNS damage following excitotoxic, oxidative, traumatic and ischaemic insults, with a predominantly apoptotic effector mechanism.

Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation.

Remyelination in CNS aggregate cultures is determined both by macrophage enrichment and the mode of demyelination. Despite the same degree of myelin loss, accumulation of MBP in anti-MOG antibody-demyelinated aggregates overtakes that of controls, while recovery is significantly delayed following IFN-gamma-induced demyelination. In antibody-treated cultures, remyelination was associated with a significant increase in culture supernatant levels of TGF-beta1, FGF-2, and PDGF-AA as well as an induction of TNF-alpha immediately following removal of the demyelinating insult.

Role for TGF-beta1, FGF-2 and PDGF-AA in a myelination of CNS aggregate cultures enriched with macrophages.

The increase in myelin basic protein (MBP) synthesis observed in brain aggregate cultures supplemented with macrophages is reflected in elevated supernatant protein levels of the key promoters of oligodendrocyte proliferation, fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-AA (PDGF-AA), during the premyelinating phase. Although supernatant levels of transforming growth factor-beta1 (TGF-beta1), the most abundant growth factor produced at the transcriptional and translational levels by phagocytic macrophages, were reduced at this stage, it was the only growth factor for which mRNA expression was increased significantly in macrophage-enriched cultures. TGF-beta1, which supports oligodendrocyte differentiation, was increased in the supernatant of macrophage-enriched cultures only after the onset of myelinogenesis.

Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity.

A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7.