3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 87
that could potentially rescue damaged neurons [79, 86], and whose production
might be enhanced by cannabinoids. For instance, Molina-Holgado et al. [87]
have recently reported that IL-1 receptor antagonist, an important anti-inflammatory
cytokine that protects against experimentally induced ischemic, excitotoxic
and traumatic brain insults, is produced in response to cannabinoid
receptor activation in primary cultured glial cells. Interestingly, cannabinoid
receptor activation failed to do this in knockout mice for this anti-inflammatory
cytokine [87].
The anti-inflammatory properties of cannabinoid agonists also involve the
activation of the CB 2 receptors which suggest an additional role of this receptor
subtype in the inflammatory processes. This is obviously of great interest
since this receptor subtype is not involved in psychotrophic effects of cannabinoids.
This importance has been renewed in the light of recent evidence indicating
that CB 2 receptors are also expressed in the brain, even in healthy conditions,
located on cerebellar neurons [88], astrocytes [89], oligodendrocytes
[78], reactive microglia [18, 19] and perivascular microglial cells [90]. Of special
interest is the case of CB 2 receptors located in microglia since these cells
are known to perform critical roles, as they are considered the resident
macrophages in the central nervous system (CNS) [91]. Initially, it was suggested
that microglial cells were involved in a protective role, eliminating died
cells and allowing regeneration of viable axons after brief episodes of neuronal
injury (i.e. physical trauma or ischemia/hypoxia). However, recent evidence
suggests that a sustained activation of microglia contributes to the pathogenesis
in chronic neurodegenerative diseases, as mentioned above (see [67, 68] for
review). Recent reports [92, 93] suggest that CB 2 receptors play an important
role in some key processes (i.e. microglial cell proliferation and migration at
neuroinflammatory lesion sites), involved in the initial steps of microglial activation
in response to infection, inflammation or tissue injury [94].
Therefore, it appears well-demonstrated that microglia, astrocytes and
oligodendrocytes respond to cannabinoid agonists, so that the beneficial
effects of these compounds in neuroinflammation/neurodegeneration might be
related to some of the following events: (1) inhibition of proinflammatory
mediator production, (2) enhancement of anti-inflammatory factor production,
(3) inhibition of microglial recruitment and (4) enhancement of astrocyte or
oligodendrocyte survival.
Vascular effects of cannabinoids
Brain damage, such as that caused by stroke or traumatic injuries, is also associated
with the release of several endothelium-derived mediators, such as
endothelin-1 (ET-1), NO and others, which affect the local vascular tone (for
review, see [95]). The major of these mediators is ET-1, which, formed at
endothelial cells, is able to produce vasoconstriction, thus limiting the blood
supply to the injured area and aggravating brain damage [96]. Cannabinoids,