3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 81
cannabinoids represent a novel potential utility of cannabinoid-based compounds
in cancer treatment in the future [1, 3].
The present chapter will address the evidence concerning the first of these
dual effects; that is, the capability exhibited by cannabinoids to influence, by
either promoting or reducing, several biochemical mechanisms leading to the
reduction of neuronal cell death by apoptosis or necrosis. We will divide the
chapter into three parts. First, we will summarize the different cellular and
molecular mechanisms that have been reported to underly the neuroprotective
effects of plant-derived, synthetic or endogenous cannabinoids. Second, we
will overview the information concerning these neuroprotective effects in
acute neurodegeneration, in particular in the two major accidental causes of
this pathology, cerebral ischemia and traumatic brain injury. Third, we will
address the same properties in chronic neurodegeneration, with emphasis on
the five disorders, PD, HD, AD, MS and ALS, where relevant information has
been recently published.
Mechanisms involved in neuroprotection by cannabinoids
The molecular mechanisms underlying the neuroprotectant properties of
cannabinoids are quite diverse and, frequently, complementary. They include
some events not mediated by cannabinoid receptors [i.e. N-methyl-D-aspartate
(NMDA) receptor antagonism, antioxidant properties] and others that are
definitively mediated by either CB 1 or CB 2 receptors including their capability
(1) to reduce processes such as glutamate release, calcium influx and/or
inflammation, (2) to stimulate γ-aminobutyric acid (GABA) action and (3) to
improve blood supply to the injured brain (for review, see [4–6]). Other additional
processes also influenced by cannabinoids, such as improvement of glucose
utilization, or alternatively the production of ketone bodies – which, produced
by glial cells, may replace glucose as the major source of neuronal energy
metabolism in ischemia (see [23, 24] for review) – or the lowering effect on
body temperature (see [25] for review), might be also considered. However,
they have been less explored in relation to their involvement in
cannabinoid-induced neuroprotection, and therefore they will not be addressed
here.
Anti-glutamatergic effects of cannabinoids
Excitotoxicity, reflected in excessive extracellular levels of glutamate and
hyperactivation of glutamate receptors, mainly the NMDA receptor subtype, is
a critical event in acute or chronic neurodegeneration (see [26] for review). It
is bidirectionally related to an uncontrolled shift in sodium, potassium and,
particularly, calcium concentrations that disrupt ionic homeostasis and leads to
severe cell swelling and death [26]. Cannabinoid agonists are certainly