Pituitary adenylate cyclase-activating polypeptide (
PACAP) is a widespread
neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous
PACAP therefore results in a variety of abnormalities. One of the important effects of
PACAP is its neuroprotective and general cytoprotective role.
PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from
PACAP-deficient mice provide evidence that endogenous
PACAP also has protective functions. Mice lacking
PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of
PACAP-deficient mice against harmful stimuli. Mice lacking
PACAP respond with a higher degree of injury in
cerebral ischemia, autoimmune
encephalomyelitis, and axonal lesion.
Retinal ischemic and excitotoxic
injuries also produce increased cell loss in
PACAP-deficient mice. In peripheral organs, kidney cell cultures from
PACAP-deficient mice are more sensitive to oxidative stress and in vitro
hypoxia. In vivo,
PACAP-deficient mice have a negative histological outcome and altered
cytokine response in kidney and small intestine
ischemia/reperfusion injury. Large intestinal
inflammation, toxic lesion of the pancreas, and
doxorubicin-induced
cardiomyopathy are also more severe with a lack of endogenous
PACAP. Finally, an increased inflammatory response has been described in subacute
endotoxin-induced airway
inflammation and in an
oxazolone-induced
allergic contact dermatitis model. In summary, lack of endogenous
PACAP leads to higher vulnerability in a number of
injuries in the nervous system and peripheral organs, supporting the hypothesis that
PACAP is part of the endogenous cytoprotective machinery.