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in particular 2-AG, are potent modulators of the vascular tone (see [97, 98] for
review), which is suggestive that they might provide neuroprotection in part
because of this property. In this sense, cannabinoids counteract the
ET-1-induced vasoconstriction, thus helping to restore blood supply to the
injured brain (see Fig. 1, and [99] for review). This effect was exerted by the
activation of CB 1 receptors since it was prevented by SR-141716 [100], which
indicates that this receptor subtype is located in brain microvasculature (see
[101] for review). In addition, as mentioned above, cannabinoid agonists are
able to reduce NO production, thus reducing the vascular effects of this additional
endothelium-derived mediator [99]. Both effects might be part of the
neuroprotective response provided by cannabinoid agonists, in particular in
cases of acute neurodegeneration such as stroke and head trauma.
Cannabinoids in acute neurodegeneration
Traumatic brain injury is the leading cause of death in young people and represents,
together with cerebral ischemia, two more frequent reasons for acute
neurodegeneration resulting in permanent disability [102, 103]. Cell death during
these acute insults is mainly necrotic and is characterized by a loss of plasma
membrane integrity leading to subsequent inflammatory events. Apoptosis,
characterized by activation of an endogenous mechanism of destructive
enzymes called caspases, may also occur during acute degeneration but always
as a secondary event. Unfortunately, neurodegeneration caused by either
ischemia or trauma is currently without a satisfactory clinical treatment,
despite several trials using compounds exhibiting anti-glutamatergic activity,
calcium-blocking actions, antioxidant properties or anti-inflammatory effects
[26, 104–108]. As cannabinoids combine all these properties, recent preclinical
studies have tried to demonstrate that they may provide neuroprotection in
acute degeneration produced by several types of accidental injuries, such as
those producing glutamatergic excitotoxicity [13, 28, 56, 88], ischemic stroke
[30, 109, 110], hypoxia [111], head trauma [15], oxidative stress [55, 56],
ouabain-induced secondary excitotoxicity [10, 50] and others (see Tab. 1 for
an overview, and [4–6] for recent reviews).
In vivo, treatment with cannabinoids reduced infarct size and associated
edema, and produced a functional improvement (reduction of neurological
deficits) in animal models reproducing acute degeneration [4–6], i.e. rodents
with global (transient) or focal (permanent or transient) cerebral ischemia
induced by occlusion of carotid and vertebral arteries or intracraneal vessels,
respectively (see [9] for review). Neuroprotection by cannabinoids was also
seen in vitro using cultured neurons subjected to hypoxia and/or glucose deprivation,
or exposed to excitotoxic stimuli, where cannabinoids increased survival
of neurons (see [6] for review). For instance, cannabinoid agonists protected
cultured rat hippocampal neurons [28] and mouse spinal cord neurons
[29] from excitotoxicity. Nagayama and coworkers [30] reported that