Biochemical Mechanisms behind Rosemary’s Benefits regarding Alzheimer’s Disease

3.2. Antioxidant Mechanisms

A number of simple in vitro experiments where the antioxidant potential of rosemary diterpenes is demonstrated include lipid peroxidation and protection of cells from oxidative cell death [73, 74].

In this respect, Hou et al. [75] have shown that carnosic acid (7) protects neuronal cells from ischemic injury by scavenging ROS. The antioxidant mechanisms of (7) and carnosol (8) are dependent on the loss of hydrogen from their phenolic hydroxyl groups leading to formation of quinone derivatives [76, 77].

In this respect, Hou et al. [75] have shown that carnosic acid (7) protects neuronal cells from ischemic injury by scavenging ROS. The antioxidant mechanisms of (7) and carnosol (8) are dependent on the loss of hydrogen from their phenolic hydroxyl groups leading to formation of quinone derivatives [76, 77].

reported to activate Nrf2, phase II detoxifying enzyme genes, and antioxidant enzymes [99, 100]. Direct interaction of (8) with cysteine residues of the nuclear factor kappa B (NF-κB) has also been demonstrated [101103]. In a similar manor, carnosic acid (7) has been shown to protect neuronal HT22 cells through activation of the antioxidant-responsive element [104]. 

The free carboxylic acid and catechol hydroxyl moieties have been shown to play critical role in these effects [104]. All the available evidence now therefore suggests that the major rosemary constituents (7 and 8) protect neurons against oxidative stress by activating the Keap1/Nrf2 pathway. Xiang et al. [104], for example, have demonstrated that (7) and (8) could protect HT22 cells against oxidative glutamate toxicity through mechanisms involving activation of the transcriptional ARE of phase II genes including heme oxygenase-1, NADPH-dependent quinone oxidoreductase, and γ-glutamyl cysteine ligase, all of which provide neuroprotection by regulating the cellular redox system.

. Moreover, carnosol (8) has been shown to enhance the glutathione S-transferase (GST) and quinone reductase activity in vivo [105]

Furthermore, antioxidant defences in AD have been found to be highly suppressed as low level of SOD [112] and reduced form of glutathione (GSH) [113, 114] as well as mitochondrial dysfunction [115] are all common features of AD. Hence, the numerous reports on the antioxidant effects of rosemary diterpenes along with their specific effect on neuronal cells through the abovementioned antioxidant mechanisms imply that they should be considered for further development as anti-Alzheimer’s agents.

Metal Chelation. High level of metal ions such as copper, zinc, and iron have been found in the amyloid plaques of AD brains [116118]. Higher millimolar level of unregulated metal ions in the brain has also been shown to arise due to age related deterioration of the blood-brain-barrier leading to unchecked access of the brain to metal ions [119]. As described in the later section, these metal ions play critical role in Aβ-induced neurotoxicity in AD. Hence, a potent metal chelative effect of a drug is an important feature of anti-AD therapy. Our own study on polyphenolic compounds in the last two decades has revealed that their biological effect including enzyme inhibition could be partly explained by their ability to chelate iron and other redox metals and, for such effect, one of the best structural features in a molecule is the orthodihydroxyl functional moiety [78–89].

The structural features of (7) and (8) are in favour of strong metal chelation properties. Carnosol (8) has been shown to inhibit Cu2+-induced LDL oxidation [120] but, most importantly, metal (e.g., iron) chelation is one of the known mechanisms of antioxidant effects. Furthermore, iron absorption from the gut is strongly suppressed by rosemary extract [121].

anti inflammatory mech

Glial cells are the major inflammatory cells of the brain which produce massive amount of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) upon activation. Numerous studies have highlighted the fact that high levels of these inflammatory cytokines are critical in the coordination of brain inflammation in AD [132, 133]. Moreover, both microglia and astrocytes have been shown to be highly regulated in AD brains [133, 134]. The potent anti-inflammatory activity of rosemary diterpenes in both the microglial cells [126, 135] and other inflammatory models therefore suggests their potential in tackling AD.

3.4. Aβ Mechanisms

Generally, amyloid plaques and neurofibrillary tangles (NFT), which are closely linked to the formation of toxic insoluble aggregates of Aβ, have shown to be the two most common pathological hallmarks of AD [136138]. The Aβ is formed from the neuronal transmembrane glycoprotein (100–130 kDa) called the amyloid precursor protein (APP). The α-, β-, and γ-secretases are the three

The multifunctional nature of rosemary diterpenes in metal chelation and ROS scavenging is thus likely to contribute to their effect against Aβ polymerisation and toxicity.

3.5. ACHE Activity

The impairment of memory and cognitive power in AD has been shown to be associated with the loss of cholinergic neurons in the cortex [171174]. Under this circumstance where the acetyl choline (ACH) activity in this region is below the normal level, one approach of therapeutic intervention in AD is to minimise the degradation of ACH by its enzyme, ACHE. Even though such drugs have limitation due to their undesirable side effects, an overall beneficial effect in cognitive improvement and behavioural symptoms have been clinically observed [175]. Szwajgier [176] has studied the effect of carnosic acid (7) against ACHE along with 35 other phenolic compounds. Interestingly, CA was identified as the most potent. In silico molecular interaction study approach on AChE inhibitors has also resulted in the identification of (7) as a potential lead drug candidate [177]. The memory enhancing effect of rosemary extract (200 mg/kg, p.o.) in the scopolamine-induced dementia model of AD has also been shown to be linked with direct effect on ACHE activity [72]. While the mRNA expression of butyrylcholinesterase (BuChE) in the cortex was inhibited, its expression in the hippocampus was enhanced by rosemary extract [72]. These effects on the expression of enzymes however could be mediated through indirect effect via other mechanisms.

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4. General Summary and Conclusion

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