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glial cells (mainly reactive microglia) and impact on neurons to induce neurodegeneration
(see [67] for review). For instance, IL-6 and TNF-α have been
shown to promote demyelination, thrombosis, leukocyte infiltration and
blood–brain-barrier disruption (see [68] for review). By contrast, glial cells
(mainly astrocytes) are able to produce prosurvival factors which play a role in
neuronal protection [69]. Both phenomena occur in ischemia [70], trauma [71],
PD [72], HD [73], AD [74, 75] and other diseases [67]. In addition, inflammation
can also elicit neurodegeneration through the activation of autoimmune
responses against brain antigens, as happens in the case of MS and other
demyelinating diseases (see [4, 76] for review). Cannabinoid agonists are able
to reduce the inflammation that occurs in these diseases. This effect is possibly
caused by local effects on glial cells, exerted by either reducing the release of
cytotoxic factors or increasing the production of prosurvival molecules (see
Fig. 1, and [4–6, 24, 25, 68] for review). This is consistent with the idea that the
endocannabinoid signaling system would play crucial roles in glial cells both in
healthy and pathological conditions (for review, see [24, 68]).
The anti-inflammatory potential of cannabinoid agonists in neurodegenerative
diseases has been recently addressed in several studies that have revealed
potent anti-inflammatory effects of selective agonists for CB 1 (arachidonoyl-2chloroethylamide,
ACEA) or CB 2 (JWH-133, JWH-015) receptors and also of
non-selective cannabinoid agonists (see [4–6, 24, 68] for review). In part, this
is the consequence of an effect of cannabinoids by protecting astrocytes and
oligodendrocytes from death, which is also beneficial for neurons [77, 78]. On
the other hand, cannabinoid agonists, possibly by activating CB 1 receptors
[79], modulate proinflammatory cytokine production by glial cells, mainly
IL-1, TNF-α, IL-6 and IL-12 which play a major role in the development of
damage in neurodegenerative/neuroinflammatory conditions, such as those
occurring in cerebral ischemia (see [4, 68] for review). Of particular interest is
the inhibitory effect of cannabinoid agonists on the production of TNF-α since
this is a major contributor to the pathophysiology of brain injury [80]. These
inhibitory effects might be exerted by inhibiting the activation of the nuclear
factor-κB (NF-κB), which is involved in the induction of cytokine gene expression.
HU-211, which does not bind to cannabinoid receptors, was able to inhibit
this transcription factor [34]. In addition, several cannabinoid agonists were
able to reduce mRNA levels for certain cytokines in lipopolysaccharide-treated
rat microglial cells but these effects were not cannabinoid receptor-mediated
[81]. Another important inflammation-related mediator is NO, which is produced
in response to immune-mediated cellular toxicity playing a role in neurodegeneration
(for review, see [1, 68]). Strategies that reduce the expression
of the inducible or neuronal forms of NO synthase may be neuroprotective (see
[25] for review). In this sense, cannabinoid agonists have been reported to
inhibit the release of NO in microglia [82], astrocytes [83], neurons [84] and
macrophages [85].
Glial cells may also secrete various trophic factors, such as the transforming
growth factor-β, the anti-inflammatory cytokine IL-10, and neurotrophins,