Comparative
neuroprotective effects of preischemic PACAP and VIP administration
in permanent occlusion of the middle cerebral artery in rats
Andrea
Tamás 1, Dóra Reglõdi 1, Zalán
Szántó 2, Balázs Borsiczky 2, József
Németh 3 & István Lengvári 1
1.
Deparments of Human Anatomy, Pécs University Medical
School, HUNGARY.
2. Experimental Surgery and
3. Pharmacology, Pécs University Medical School, HUNGARY.
Submitted:
March 18, 2002
Accepted: March 27, 2002
Keywords:
PACAP; VIP; neuroprotection; focal cerebral ischemia
Abstract
OBJECTIVE:
Pituitary adenylate cyclase activating polypeptide (PACAP)
and vasoactive intestinal polypeptide (VIP) belong to the
same peptide family, and both neuropeptides have been shown
to exert in vitro and in vivo neurotrophic and neuroprotective
effects. The aim of the present study was to investigate and
compare the protective effects of PACAP and VIP in permanent
focal cerebral ischemia in rats. The effect on the progression
of the cerebral infarct was also studied.
METHOD:
Male rats were injected 450 pmol PACAP or VIP dissolved in
physiological saline intracerebroventricularly, preceding
the occlusion of the middle cerebral artery. Control animals
received vehicle treatment. Permanent focal ischemia was induced
by the intraluminal filament occlusion of the middle cerebral
artery. Animals were sacrificed 12 or 24 hours after the onset
of ischemia, and infarcted brain areas were determined by
staining bran sections with triphenyl-tetrazolium chloride.
RESULTS:
Twelve hours after ischemia, the infarcted brain volume resulted
to be 14.8% in the control group, 15.3% in the VIP-treated
group and 5.8% in the PACAP-treated animals. Twenty-four hours
after middle cerebral artery occlusion, the infarcted brain
volumes were 21.5%, 20.7% and 14.3% in the control, VIP and
PACAP-treated animals, respectively.
CONCLUSION:
Our results provide further evidence for the neuroprotective
effects of PACAP38 as given in form of a preischemic bolus.
It slows down the progression of the evolution of the infarct
and reduces the final infarct size. In contrast, a related
peptide, VIP, does not have neuroprotective effects under
the same experimental conditions.
Introduction
ABBREVIATIONS
PACAP
- Pituitary adenylate cyclase activating polypeptide
VIP - Vasoactive intestinal peptide
MCAO - Middle cerebral artery occlusion
Introduction
There is an increasing number of candidate therapeutic agents
that are proven to be neuroprotective in animal models of stroke.
In addition to classical neurotrophic factors, some neuropeptides
have been shown to exhibit neurotrophic and neuroprotective
effects [1–3], with vasoactive intestinal polypeptide (VIP)
and pituitary adenylate cyclase activating polypeptide (PACAP)
being among the main candidates [1]. They belong to the same
peptide family (secretin/glucagon/VIP family), show closest
structural homology among these related peptides and have numerous
similar effects [4–6]. In vitro, both VIP and PACAP stimulate
neuronal survival, regulate mitogenic activity and differentiation
of embryonic neuronal cultures, and protect neurons against
various toxic agents [1,4,6].
VIP
and PACAP have also in vivo neurotrophic and neuroprotective
effects. Both play a role in the development of the brain [7–10].
VIP analogs are protective in white matter lesions in leukomalacia
[11,12], enhance cognitive functions in Alzheimer-related models
[13,14], while antagonists retard neonatal behaviors and produce
microcephaly [7,8]. Recent studies show neuroprotective effects
of PACAP in animal models of other cerebral pathology. PACAP
protects hippocampal neurons in global ischemia [15] and promotes
the survival of forebrain cholinergic neurons after fornix transection
[16].
We
have previously demonstrated the protective effects of PACAP
in a rat model of focal ischemia: PACAP reduced the infarct
size when given postischemic, in transient Middle Cerebral Artery
Occlusion (MCAO) [17]. This administration paradigm was in accordance
with studies showing that most compounds investigated as possible
treatments for stroke in animal models are maximally effective
given as initial bolus followed by constant intravenous infusion
[18]. However, for practical reasons it would be more acceptable
to give treatment in the form of a single or intermittent bolus
[18]; examination of the effectiveness of drugs as bolus injections
is therefore reasonable. According to our previous observations,
systemic administration of postischemic intravenous bolus injection
of PACAP38 alone did not prove to be effective (unpublished
observations). Similar observation was made in a model of global
ischemia, due to a binding protein in the blood [15,19,20].
This, and the known potent peripheral vasodilator effect of
PACAP restrict the systemic administration of higher doses of
the peptide at present [6, 21]. Therefore, to investigate the
effects of a single bolus injection, we chose to use intracerebroventricular
administration in the present study.
The
efficacy of a candidate neuroprotective drug may be very different
under various experimental conditions: type of the occlusion
(transient or permanent), beginning of administration, temperature
and rat strain have been documented to influence the effects
of drugs [22–27]. In order to extend our knowledge on the
neuroprotective efficacy of PACAP in cerebral ischemia, we investigated
the effects of PACAP38 in permanent focal ischemia, when given
as a single intracerebroventricular bolus preceding the onset
of the insult. A neuroprotective drug that is effective when
given as a single preischemic bolus injection is especially
important in certain neurosurgical interventions, where the
time of the intervention is restricted to short intervals due
to the risk of infarction [28]. In the present study we also
examined the neuroprotective effect of the same doses of VIP,
and the effect of both peptides on the progression of the infarct
size, as measured 12 and 24 hours after the occlusion of the
middle cerebral artery.
Material and methods
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