Rosemary (Rosmarinus officinalis L.) is one of the most economically important species of the family Lamiaceae. Native to the Mediterranean region, the plant is now widely distributed all over the world mainly due to its culinary, medicinal, and commercial uses including in the fragrance and food industries. Among the most important group of compounds isolated from the plant are the abietane-type phenolic diterpenes that account for most of the antioxidant and many pharmacological activities of the plant. Rosemary diterpenes have also been shown in recent years to inhibit neuronal cell death induced by a variety of agents both in vitro and in vivo. The therapeutic potential of these compounds for Alzheimer’s disease (AD) is reviewed in this communication by giving special attention to the chemistry of the compounds along with the various pharmacological targets of the disease. The multifunctional nature of the compounds from the general antioxidant-mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (Aβ) formation, polymerisation, and pathologies is discussed.

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The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer’s Disease

Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats

The nervous system is especially vulnerable to reactive oxygen species (ROS)-mediated injury for the following reasons. (1) High oxygen consumption of the brain for high energy needs, that is, high O2 consumption, results in excessive ROS produced. (2) Neuronal membranes are rich in polyunsaturated fatty acids (PUFA), which are particularly vulnerable to free radical attack. (3) The ratio of membrane surface area to cytoplasmic volume is high. (4) Specialized neuronal conduction and synaptic transmission activity depend on efficient membrane function. (5) Extended axonal morphology is prone to peripheral injury. (6) Neuronal anatomic network is vulnerable to disruptions. (7) The excitotoxic glutamate is the major effector that causes oxidative stress (OS). (8) The high Ca2+ traffic across neuronal membranes and interference of ion transport increase intracellular Ca2+, often leading to OS. (9) Auto-oxidation of neurotransmitters can generate O2 and quinones that reduce glutathione. (10) Iron is formed throughout the brain, and brain damage readily releases iron ions capable of catalyzing free radical reactions. (11) Antioxidant defense mechanisms are modest, in particular, low levels of catalase, glutathione peroxidase, and vitamin E. (12) ROS directly downregulate proteins of tight junctions and indirectly activate matrix metalloproteinases (MMP) that contribute to open the blood–brain barrier (BBB). (13) Activated microglia produce ROS and cytokines in a perpetual process. (14) Cytochrome P450 produces ROS. (15) Loss of trophic support can activate NADPH oxidase, which increases ROS. (16) The presence of hemoglobin within the neural tissues secondary to spontaneous, iatrogenic, or traumatic causes is neurotoxic. Heme and iron are released and promote ROS. (17) Neuronal mitochondria generate O2. (18) The interaction of NO with superoxide can be implicated also in neuronal degeneration. (19) Neuronal cells are nonreplicating and thus are sensitive to ROS. In comparison with other organs, the neuronal network may be especially vulnerable to ROS-mediated injury because of the following anatomic, physiological, and biochemical properties of the brain.

Why Is the Nervous System Vulnerable to Oxidative Stress

Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu) are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA). A further structural diversity of RA derivatives in some plants such as Salvia miltiorrhiza Bunge is a form of RA dimer, salvianolic acid-B (SA-B), that further give rise to diverse salvianolic acid derivatives. This review provides a comprehensive perspective on the chemistry and pharmacology of these compounds related to their potential therapeutic applications to dementia. The two common causes of dementia, Alzheimer's disease (AD) and stroke, are employed to scrutinize the effects of these compounds in vitro and in animal models of dementia. Key pharmacological mechanisms beyond the common antioxidant and anti-inflammatory effects of polyphenols are highlighted with emphasis given to amyloid beta (Aβ) pathologies among others and neuronal regeneration from stem cells.

https://www.mdpi.com/1422-0067/19/2/458/pdf

Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer's and Vascular Dementia Drugs.

Grape seed proanthocyanidin lowers brain oxidative stress in adult and middle-aged rats.

With aging, the brain undergoes neuronal loss in many areas. Although the loss of cells in the cerebral cortex, in particular the frontal cortex, has been recognized with aging, the influence of synaptic losses has a larger impact on cognitive decline. Much of the recent research on animals, as well as humans, has been aimed at slowing the cognitive decline through enrichment, and it has been found that the key factors are antioxidants and exercise. Several reports support the concept that regular supplementation of vitamin E and physical activity from as early as middle age can slow the cognitive decline observed during the later years. A few studies have also suggested that exercise is analogous to acetylcholine esterase inhibitors that are also used extensively to treat cognitive impairment and dementia in Alzheimer's disease. In addition, reports also support that vitamin E and exercise may act synergistically to overcome free radical injury and oxidative stress in the aging brain.

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Aging brain: prevention of oxidative stress by vitamin E and exercise.

Decline in cognition is one of the earliest signs of normal brain aging. Several dietary and non-pharmacological approaches have been tested to slow down this process. The aim of the present study was to assess the influence of grape seed proanthocyanidin extract (GSPE) either individually or in combination with swimming training on acetylcholine esterase activity (AChE) and m1 acetylcholine receptor (m1AChR) on the extent of cognitive decline with aging. The experimental protocol included the oral administration of GSPE (400 mg/kg body weight) for 14 weeks to 4 (adult) and 18-month-old (middle-aged) male Wistar rats along with swimming training. They were subjected to behavioral testing followed by biochemical and immunohistochemical analysis. The results demonstrated that GSPE supplementation and swimming training either individually or in combination had an improvement on acquisition and working memory with reduced AChE activity in the medial prefrontal cortex (mPFC) and hippocampus (HC). Immunohistochemical and qRT-PCR evaluation showed an increase in m1AChR protein and mRNA in the CA1 region of HC and also mPFC upon swimming training with GSPE treatment. These beneficial and synergistic effects of GSPE and swimming training are suggestive as interventions in modulating the cognitive function, with GSPE alone being more suitable for middle-aged individuals.

Grape Seed Proanthocyanidin and Swimming Exercise Protects Against Cognitive Decline: A Study on M1 Acetylcholine Receptors in Aging Male Rat Brain.

It is frequently accepted that grape seed proanthocyanidins (GSPs) are efficient antioxidants and beneficial in improving cognitive functions. However, diabetes (T1DM)-associated declines in learning and memory and the possibilities of GSPs in overcoming this loss needs to be examined. The present study was designed to examine the correlation, if one exists, between cognitive behavior and neuronal survival in the prefrontal cortex (PFC) in streptozotocin (STZ)-induced diabetic Wistar rats as well as to further clarify whether the correlation exists. Also this study aimed to determine whether neurological structural changes in the PFC and pancreatic β-cells can be restored by grape seed proanthocyanidin extract (GSPE). At the end of 8 weeks, cognitive tests that rats given supplementation of GSPE and insulin had greater improvement in their spatial learning and memory skills and improved neuronal survival in the PFC and pancreatic β-cells compared to rats supplemented with either insulin or GSPE alone. Expression of Bax in the PFC was increased in the diabetic rats while Bcl-2 expression was decreased, and GSPE and insulin treatment reversed the expression of apoptotic proteins. Our findings on GSPE, a natural product, as a form of adjuvant therapy together with insulin treatment is suggestive of the existence of synergism between the two in attenuating diabetic complications in the pancreas and PFC.

Grape seed proanthocyanidin extract and insulin prevents cognitive decline in type 1 diabetic rat by impacting Bcl-2 and Bax in the prefrontal cortex

Differential expression of the cerebral cortex proteome in physically trained adult rats

The last two decades has witnessed accumulating evidences in favour of oxidative stress as a causative link between normal brain aging and several neuropathological conditions. Reactive oxygen species (ROS) is considered a major factor contributing to decline in brain function with aging. Cognitive impairment and oxidative stress are common occurrences in old age and are often traceable to events such as increased lipid peroxidation and protein oxidations in specific cognitive regions of the brain, the hippocampus and cerebral cortex. With the advent of various cognitive tests, oxidative pathology is further confirmed by behavioural changes in animal and humans as well. While much of the biomedical research is concentrating on methods to cure aging related neurodegeneration and cognitive decline, biogerontologists are seeking something larger with a view to finding ways to prevent it at its root. Here we discuss and highlight the possibilities of curtailing the cognitive deficits during normal and pathological aging through evidences in favour of vitamin and non-vitamin supplements—in an effort to run the biological clock backwards and extend healthy brain function.

Sambe Asha Devi

Papers

Aging brain: prevention of oxidative stress by vitamin E and exercise.

Grape Seed Proanthocyanidin and Swimming Exercise Protects Against Cognitive Decline: A Study on M1 Acetylcholine Receptors in Aging Male Rat Brain.

Grape seed proanthocyanidin extract and insulin prevents cognitive decline in type 1 diabetic rat by impacting Bcl-2 and Bax in the prefrontal cortex

Differential expression of the cerebral cortex proteome in physically trained adult rats

Oxidative Stress and the Brain: An Insight into Cognitive Aging