Biomedical Engineering Reference
In-Depth Information
6. Neuroprotective Effect of Naloxone Stereoisomers
on Dopaminergic Neurons in the Infl ammation-Related
Model of PD
The establishment of both in vitro and in vivo infl ammation-related models
of PD has enabled the search for and study of the mechanism of action
responsible for a variety of neuroprotective agents. Of particular interest
is the neuroprotective effect of the naloxone stereoisomers. In the in vitro
neuron-glia culture system, 1
M
(-)-naloxone afforded signifi cant protection
of dopaminergic neurons against LPS-induced degeneration. Interestingly,
(+)-naloxone, which lacks opioid receptor binding activity, was equally effec-
tive
(69)
. The neuroprotective effect of naloxone was most likely unrelated to
the opioid system because both compounds effectively inhibited the activation
of microglia and their production of NO, TNF-
ยต
, and especially the superoxide
free radical (
69
,
82
;
Fig. 2
). The in vitro observations were confi rmed by in vivo
studies where systemic administration of naloxone with an osmotic minipump
reduced the loss of nigral dopaminergic neurons induced by LPS injection
(67
,
68)
. Again, both (-)-naloxone and (+)-naloxone were equally effective
(67)
. Interestingly, over the last several decades, several groups have described
nonopioid effects of (+)-naloxone in various systems
(71-74)
. In addition,
Simpkins and associates have reported that both naloxone stereoisomers
are capable of suppressing the chemoattractant-induced activation of human
neutrophils
(75
,
76)
. Therefore, it is possible that naloxone, regardless of its
stereoconfi gurations, is an effective modulator of immune cell activity. The
appreciation of nonopioid and immune modulatory activity of naloxone and,
at the same time, the increasing awareness of the role of infl ammation in many
disease conditions, may help redefi ne the mechanism of action for the observed
effi cacy of naloxone in the experimental treatment of a variety of pathological
conditions. For example, whether the benefi cial effects observed for naloxone
in the treatment of spinal cord and traumatic brain injuries and myocardiac/
cerebral stroke are related to any potential inhibitory effect on the secondary
inflammatory response occurred following the initial phase of cell death
remains to be examined
(17-19)
. Interestingly, in the experimental treatment
of Alzheimer's disease, naloxone was found to be much more promising in
younger patients
(77
,
78)
than in more advanced cases
(79
,
80)
. It would be
of great interest to determine whether these results imply that reduction by
naloxone of the infl ammatory response at an earlier stage of the progression of
the disease will have a more favorable fi nal outcome. Similarly, the benefi cial
effect of naloxone in the experimental treatment of bacterial sepsis may also be
related to its negative modulatory effect on the immune cells, although it may be
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