Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog
Introduction
Alzheimer's disease (AD) is characterized by a progressive deterioration of cognitive processing, especially associative (e.g. identification of people, places, and events) and spatial (location in one's environment) memories. Accompanying these dysfunctions is a marked and dramatic depletion of central cholinergic neurons primarily in structures concerned with cognitive processing 1, 2, 3, 4. These brain structures include the nucleus basalis of Meynert (NBM), septal nuclei, temporal cortices, and the CA1 region of the hippocampus. Within these structures, choline acetyltransferase (ChAT), a marker for cholinergic activity, is depleted by up to 90% [5]. Animal models prepared with ibotenic acid or electrolytic lesions to the septal nuclei and the nucleus basalis magnocellularis (non-primate mammalian equivalent of NBM), show a disruption of performance in associative and spatial learning paradigms 6, 7. Based upon loss of cholinergic neurotransmission in AD patients, pharmacological blockade of the cholinergic system has often been used to create an animal model of AD. Specifically, the muscarinic receptor antagonist, scopolamine hydrobromide (scop), induces learning and memory deficits when administered peripherally or centrally 8, 9, 10, 11.
Our laboratory has recently discovered a new angiotensin receptor subtype, termed AT4 [12], that selectively binds the hexapeptide angiotensin II (3–8) (Ang IV: Val-Tyr-Ile-His-Pro-Phe) 13, 14. A role in learning and memory has been postulated for the AT4 receptor based upon several observations. (1) There are high concentrations of AT4 receptor sites in areas of rat and guinea pig brain classically associated with cognition, including the hippocampus and neocortex [15], and the hippocampus, neocortex, and NBM in the monkey [16]. (2) Central administration of Ang IV has been shown to facilitate retention of a passive avoidance-conditioning task while an AT4 antagonist disrupts this process 17, 18. And (3), icv application of Ang IV selectively activates c-Fos in pyramidal and granular cells of the hippocampus suggesting that these cells, which are vital to cognitive function, are responsive to AT4 agonists [19]. Given the short half-life of native Ang IV, our laboratory deemed it useful to synthesize a metabolically stable analog, with high affinity for the AT4 receptor (Kd=3×10−12 M) and low affinity for the AT1/AT2 receptors [20]. This was accomplished with the synthesis of norleucine1-Ang IV (Nle1-Ang IV).
The circular water-maze task has been utilized as a measure of spatial memory and is sensitive to the cognitive disruption induced by scop [21]. Thus, the present study tested the effects of Nle1-Ang IV on spatial learning and memory in scop treated animals. We hypothesized that scop-induced deficits in acquisition of the circular water-maze task would be reversed by central administration of Nle1-Ang IV.
Section snippets
Animals and surgery
Twenty-four female Sprague-Dawley rats (Charles River derived; 250–350 g) were housed individually in an AAALAC-approved vivarium maintained at 22±1°C, with an alternating 12:12 h light/dark cycle initiated at 0700 h. All animals had ad libitum access to water and Purina laboratory rat chow. Food was removed the night before surgery. Each animal was anesthetized with Equithesin (3.5 mg/kg pentobarbital IP, Jensen-Salsbury laboratory), and an intracerebroventricular (icv) guide cannula (PE 60,
Results
Fig. 1A shows the mean (±SEM) latencies to find the submerged platform during acquisition training. The scop-treated animals that subsequently received aCSF performed poorly as compared with members of the control group (aCSF followed by aCSF); however, the scop-treated rats that received Nle1-Ang IV attained the low latencies achieved by the controls. Specifically, a 3 (groups)×8 (days) ANOVA revealed a groups effect (F2,19=6.12, P<0.01); a days effect (F7,133=25.12, P<0.001); and a
Discussion
Although the brain renin–angiotensin system has been implicated in cognitive processes, results from human and animal studies have been inconclusive. Specifically, it has been reported that humans given angiotensin converting enzyme (ACE) inhibitors to control hypertension, also reveal enhanced cognitive performance and `feelings of well being' 23, 24, 25. In agreement with these reports, administration of ACE inhibitors to naive, aged, and scopolamine-treated rodents has been shown to
Acknowledgements
The authors wish to thank Korrie Foley and Ryan Nielson for their assistance in collecting these data. This research was supported by funds provided by Hedral Therapeutics, the Edward E. and Lucille I. Laing Endowment, and Washington State University.
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2013, PeptidesCitation Excerpt :Ang IV was proved to bind to insulin-regulated aminopeptidase (IRAP) as an endogenous blocker [1]. Instead of being with no function, Ang IV was found to cause significant effects on enhancing/improving memory [3,22,32]. In 2004, Stragier et al. reported that angiotensin II tended to transform to Ang IV more than to stop at angiotensin III in neurons [39].
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2012, PeptidesCitation Excerpt :Ang IV (Val–Tyr–Ile–His–Pro–Phe) was produced from the cleavage of angiotensin III (Ang III) and originally supposed to be the end product of renin-angiotensin system. Instead of being with no function, Ang IV was found to be an endogenous IRAP blocker and thereby caused a significant effect on enhancing/improving memory [6,23,33]. In 2004, Stragier et al. reported that angiotensin II tended to transform to Ang IV more than to stop at angiotensin III in neurons [36].