Research reportAttenuation of scopolamine-induced learning deficits by LVV-hemorphin-7 in rats in the passive avoidance and water maze paradigms
Introduction
Angiotensin IV (Ang IV), a hexapeptide corresponding to residues 3–8 of angiotensin II (Ang II), mediates biological effects that are independent of the classical angiotensin system [29]. Ang IV binds with high affinity to a pharmacologically distinct binding site, termed the AT4 receptor [5], [6]. We have recently identified the AT4 receptor as the transmembrane enzyme insulin regulated aminopeptidase (IRAP) via mass spectral analysis of tryptic peptides generated from AT4 receptor protein purified from bovine adrenal membranes [1]. Analysis of the biochemical and pharmacological properties of IRAP confirm that it is the AT4 receptor.
Both acute and chronic infusions of Ang IV or its stable analogues, Nle1-Ang IV and Nle1-γ-Tyr2-Ang IV (where γCH2NH bond) into the cerebral ventricles has been shown to facilitate memory retention and retrieval in rats in both the passive avoidance and water maze paradigms [31]. In two rat models of amnesia, induced by either central scopolamine administration or bilateral perforant pathway lesion, the Ang IV analogues reversed performance deficits detected in the water maze paradigm [22], [23], [31]. These effects are thought to be mediated by binding of the Ang IV peptides to the AT4 receptor or IRAP.
The AT4 receptor/IRAP has a distinct distribution pattern in the brain and is found in regions associated with cognitive, sensory and motor function. In the human brain, high levels of IRAP are found in the basal nucleus of Meynert, in the CA1 to CA3 regions of the hippocampus, and throughout the neocortex, a distribution that closely resembles cholinergic neurons and their projections [4]. In comparative studies we observe that the distribution of IRAP is highly conserved in the brains of sheep [18], macaque monkey [20] and guinea pig [17] and is abundant in many of the same regions as in the human brain. This is consistent with the demonstrated role of AT4 receptor/IRAP in facilitating memory and learning.
We have previously isolated a decapeptide, LVV-hemorphin-7 (LVV-H7), from the sheep cerebral cortex [19] which bound with high affinity to IRAP. This AT4 ligand, although structurally distinct from Ang IV, exhibits many of the same effects as the hexapeptide in a number of in vitro assays including stimulating cellular proliferation [21], facilitating K+-evoked acetylcholine release in hippocampal slices [14] and competitively inhibiting the catalytic activity of IRAP [1]. However, the ability of LVV-H7 to overcome cognitive deficits in vivo has not been explored. In the present study we investigated the effect of LVV-H7 on memory deficits induced by scopolamine utilizing two behavioural paradigms, the passive avoidance conditioning and the water maze tasks.
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Animals and surgery
Male Sprague–Dawley rats (230–280 g), obtained from Animal Resource Centre, Western Australia, were housed individually in an animal housing facility maintained at 20 °C, with an alternating 12:12 h light/dark cycle initiated at 07:00 h. All animals had ad libitum access to water and standard rat chow. Each animal was anaesthetized with Equithesin (3.0 ml/kg administered 1:1 with normal saline) and an intracerebroventricular (ICV) cannula (23-gauge needle) was stereotaxically implanted above the
Water maze
A statistically significant treatment effect was observed in both latency (F2,140=27.271, P<0.001) and swim distance (F2,148=28.839, P<0.001) to find the submerged platform. Post hoc analysis revealed that during the days of acquisition (days 3–7), the 70 nmol scopolamine-treated rats took significantly longer to find the submerged platform (t=6.698, P<0.001) and travelled longer distances (t=4.391, P<0.001) compared to members of the control group. Rats treated with 1 nmol LVV-H7 after
Discussion
This study clearly demonstrates that LVV-H7 attenuates the deleterious effects of scopolamine on learning performance in two different behavioral paradigms, which involves fear-conditioning and place learning. During the acquisition phase of the water maze task, daily intracerebroventricular infusions of 1 nmol of LVV-H7 25 min after scopolamine treatment produced marked improvement in both the latency and distance swum in order to locate the submerged platform using visual cues. This improvement
Acknowledgements
This work is supported by an NHMRC block grant (#983001).
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