Study on the Role of Central Renin- Angiotensin System (RAS) in Memory Function and its Interaction with Brain Derived Neurotrophic Factor (BDNF)

Abstract

The peripheral Renin Angiotensin System (RAS) mediates a number of physiological responses including blood pressure, sodium and body water balance, cyclicity of reproductive hormones and sexual behaviors and pituitary gland hormones. The precursor, angiotensinogen, is acted upon by the enzyme renin to form angiotensin I which then converted into angiotensin II (Ang II) by angiotensin converting enzyme (ACE). The octapeptide Ang II elicits various physiological effects via activation of angiotensin type 1 (AT1) receptors (Gard, 2002; McKinley et al., 2003). The RAS participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardial infarction and diabetic nephropathy (de Gasparo et al., 2000). Based on this, two therapeutic strategies targeting RAS have been developed successfully with the aim to reduce activity of RAS. The angiotensin converting enzyme (ACE) inhibitors and AT1 receptor blockers have been in clinical use for the treatment of hypertension and other cardiovascular ailments (de Gasparo et al., 2000). Studies have shown the presence of intrinsic RAS in the brain which is independent of peripheral RAS (McKinley et al., 2003; Paul et al., 2006). All the components of the RAS like precursor, processing enzymes, various peptides and receptor systems have been identified in the variety of brain structures (Wright and Harding, 2004; Baltatu et al., 2011).The observation that none of the component of peripheral RAS can cross blood brain barrier and the identification of separate RAS in the brain, led to the discovery of various physiological and pathological roles played by central RAS. Ang II exerts profound physiological and behavioural effects by acting on AT1 receptor in the brain. These actions include stimulation of water and sodium intake, vasopressin secretion, increased blood pressure and modulation of baroreflexes (Wright and Harding, 2004). Furthermore, central effects of Ang II involve modulation of noradrenergic, substance P and glutamatergic pathways (Mayorov, 2011). Recent clinical observation showed that antihypertensive therapy with ACE inhibitors and AT1 receptor antagonist improves memory function independent of their blood pressure lowering effects (Fogari et al., 2003; Saxby et al., 2008; Li et al., 2010; Davis et al., 2011). These findings suggest a possible involvement of central RAS in the modulation of cognitive function. Further, ACE and angiotensin receptors were reported to be present in the cortex and hippocampus, the brain regions important for learning and memory function. Post mortem analysis of Alzheimer’s disease (AD) brain also revealed elevated ACE and angiotensin screening of potential antiamnesic agents (Nordberg et al. 1992; Sakurai et al., 1998; Jeong et al., 2008). AD is characterized by abnormalities in glucose metabolism and reduced glucose utilization in brain (Wyper et al., 1993; Arnaiz et al., 2001). Disturbed energy metabolism is intricately associated with increased oxidative stress that results in oxidation of biomolecules and initiates excitotoxic neuronal cell damage (Nitsch and Hoyer, 1991; Lannert and Hoyer, 1998). On the other hand, reduction in brain glucose below a critical level also affects cholinergic system. This decreases the rate of acetylcholine synthesis by lowering concentrations of acetyl-coenzyme A, a derivative of glucose (Terwel et al., 1995; Prickaerts et al., 1999). AD and other types of dementia, besides above stated characteristics are also associated with reduced cerebral blood flow due to vascular amyloidosis, oxidative stress and endothelial dysfunction (Prohovnik et al., 1988; O’Brien et al., 1992). These pathological aspects of AD are closely mimicked in rats after subdiabetogenic intracerebroventricular injection of streptozotocin (STZ) which leads to progressive deficits in learning and memory (Prickaerts et al., 1999; Sonkusare et al., 2005, Awasthi et al., 2010). Therefore, the present study utilized scopolamine and STZ induced memory impairment models to elucidate the mechanism of modulation of memory function by central RAS especially in context of oxidative stress, cholinergic dysfunction, cerebral hypoperfusion and alteration in brain energy metabolism, the factors reported to play an important role in pathophysiology of clinical dementia. Brain derived neurotrophic factor (BDNF) plays an important role in the synaptic plasticity and long-term potentiation, which form the fundamental basis of learning and memory function (Rex et al., 2006). Therefore, the present study also explored the influence of central RAS on BDNF level in memory impairment models. The outcome of this work will have a greater translational relevance in the treatment of cognitive impairment associated with cardiovascular disease and metabolic syndrome. Therefore, the precise information of involvement of central RAS in learning and memory will help in focusing those medications which apart from acting as antihypertensive can also impart neuroprotection as has been observed in PROGRESS clinical trial with perindopril, an ACE inhibitor.