The Implications of Angiotensin-Converting Enzymes and Their Modulators in Neurodegenerative Disorders: Current and Future Perspectives

Abstract

Angiotensin converting enzyme (ACE) is a dipeptidyl peptidase transmembrane bound enzyme. Generally, ACE inhibitors are used for the cardiovascular disorders. ACE inhibitors are primary agents for the management of hypertension, so these cannot be avoided for further use. The present Review focuses on the implications of angiotensin converting enzyme inhibitors in neurodegenerative disorders such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and diabetic neuropathy. ACE inhibitors such as ramipril, captopril, perindopril, quinapril, lisinopril, enalapril, and trandolapril have been documented to ameliorate the above neurodegenerative disorders. Neurodegeneration occurs not only by angiotensin II, but also by other endogenous factors, such as the formation of free radicals, amyloid beta, immune reactions, and activation of calcium dependent enzymes. ACE inhibitors interact with the above cellular mechanisms. Thus, these may act as a promising factor for future medicine for neurological disorders beyond the cardiovascular actions. Central acting ACE inhibitors can be useful in the future for the management of neuropathic pain due to following actions: (i) ACE-2 converts angiotensinogen to angiotensin(1-7) (hepatapeptide) which produces neuroprotective action; (ii) ACE inhibitors downregulate kinin B1 receptors in the peripheral nervous system which is responsible for neuropathic pain. However, more extensive research is required in the field of neuropathic pain for the utilization of ACE inhibitors in human.

Brain Renin–Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity

“…One-way ANOVA followed by Tukey's post-tests were performed, **p < 0.01, ***p < 0.001, n = 4 for each group angiotensin receptors (AT 1 -R and AT 2 -R) and regulates not only blood pressure, cerebral blood flow, and homeostasisassociated behaviors [35][36][37], but also motor activity, learning, and memory [38,39]. The ACE inhibitor, perindopril, is able to penetrate the blood-brain barrier and modulate striatal DA synthesis and release [11], and prevents the development of Alzheimer's and Parkinson's disease [40,41]. Our results unequivocally showed that perindopril decreased the expression of striatal Ang II and attenuated METH-induced hyperlocomotor, suggesting the involvement of ACE and Ang II in the formation of hyperlocomotor induced by METH.…”

Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis

“…It is known that angiotensin receptors are expressed in nociceptive processing brain and spinal cord areas and drugs that block some of these receptors (AT1Rs) are strongly neuroprotective. The AT2 receptor is upregulated in injured nerves and their DRGs . Angiotensinogen is processed into eight smaller proteins and peptides with known roles in the renin‐angiotensin system (RAS), including angiotensin‐1, angiotensin‐2, angiotensin‐3, and angiotensin 1‐7.…”

Genetic analysis of indel markers in three loci associated with Parkinson's disease

“…It was originally reported that the ACE activity levels in D/D carriers were approximately twice those found in I/I genotype individuals [ 34 ]. Therefore, this indel polymorphism was used as a marker for studying associations with pathophysiological conditions, including neurodegenerative diseases, such as PD [ 10 ]. Moreover, the ACE indel polymorphism in the Australian Caucasian population was not associated with PD in the first association study [ 35 ].…”

“…Angiotensin converting enzyme (ACE), a membrane-bound zinc metallopeptidase, regulates blood pressure and blood volume by converting angiotensin I to angiotensin II and by degrading bradykinin. Previous studies have suggested that it may be involved in the pathogenesis of neurodegenerative disorders such as PD, AD, Huntington’s disease, and autism [ 10 , 11 ]. Furthermore, the primary loss of substance P due to ACE hydrolysis has been shown to be a contributing factor in the pathogenesis of PD [ 12 – 14 ].…”