Antioxidant activity of medicinal plant compounds and aminoacids for prevention of Alzheimer's disease ‎

Dobrina Tsvetkova^1*, Ivanka Kostadinova²

¹Department of Pharmaceutical Сhemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria. ²Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria.

Correspondence: Dobrina Tsvetkova, Department of Pharmaceutical Сhemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria. [email protected]

---

ABSTRACT

The chronic progression of neurodegeneration is the main characteristic in the development of Alzheimer's disease. The prevention of brain from the neuronal damage by use of phytocompounds with antioxidant activity is an important therapeutic approach for the delay of the neuronal degeneration. The aim of current work is to summarize the data for types of plant compounds possessing antioxidant potential against Alzheimer's disease. From the results it is obvious that the more important phytocomponents with benefitial effect towards oxydative stress in Alzheimer's disease include: 1) flavonoids: quercetin, epigallocatechin-3-gallate, moringine, magnolol, honokiol, kaempferol, isorhamnetin, myricetine; 2) non-flavonoid compounds: Curcumine, Resveratrol, Caffeinc acid, Ferulic acid, Rosmarinic acid; 3) alkaloids: Arecoline, Caffeine, Galantamine, Huperzine A, Morphine, Nicotine, Piperine. Promising antioxidant effect against Alzheimer's disease exhibit the extracts from the different medicinal plants, such as Acorus calamus  L., Angelica sinensis L., Asparagus racemosus L., Azima tetracantha Lam, Berberis aquifolium Pursh, Berberis vulgaris L., Camelia sinensis (L.) Kuntze, Centella asiatica L., Citrus aurantium L., Coffea arabica L., Convolvulus pluricaulis Choisy, Coptis chinensis Franch, Curcuma longa L., Daucus carota L., Eryngium campestre L., Eryngium planum L., Galanthus caucasicus (Baker) Grossh., Galanthus nivalis L., Galanthus woronowii Losinsk, Huperzia serrata (Thumb. ex Murray) Trevis., Glycyrrhiza glabra L.  Hydrastis canadensis L., Juglans regia L., Lavanduila angustifolia Mill, Leucojum aestivum L., Lycoris radiata (L’Her.) Herb, Narcissus tazetta L., Morus alba L., Panax notoginseng (Butkill) F.H.Chen, Phyllanthus emblica L., Piper longum L., Piper nigrum L.,Vitis vinifera L., Zingiber officinalis L. Antioxidant effects exert L-Arginine, L-Histidine, L-Isoleucine, L-Serine, L-Tryptophan, L-Tyrosine, L-Cysteine, L-Methionine‎.

 

Keywords: Alzheimer's disease, Phytocompounds, Plants, Antioxidants, Aminoacids

---

Introduction  

Oxydative stress

One of the important pathogenetic hypotheses for the develpment of progressive neurodegenerative Alzheimer's disease is the oxidative stress hypotheses. It has been found that there is a dynamic balance between the free radical formation and the function of protective antioxidant systems (superoxid-dismutase, catalase, glutathione-peroxidase, glutathione-reductase). The increased  levels of free radicals lead to oxidative stress, which is at the base of the pathogenesis of neurodegenerative diseases [1], such as Alzheimer [2], Parkinson [3], Huntington, Amyotrophic lateral sclerosis (Lou-Gerich's disease) [1], and for the development of the disorders, such as atherosclerosis, cancers, such as brain gliomas and meningiomas [4], chronic renal failure, Daun syndrome, diabetes type 1 and 2, hypertension, schizophrenia, vasculas diseases, psoriatic arthritis [5], brain aneurysm [6]. Under lipid peroxidation polyunsaturated fatty acids cause the formation of oxidation product malondialdeyhde in erythrocyte membrane [7]. Oxidative stress causes pathological changes in aging [8].

The most important hallmarks of Alzheimer's disease are the beta-amyloid plaques, tau protein tangles and oxidative stress [2], that both with inflammation play an important role in the pathogenesis of early and late phase of Parkinson disease [3].

By the oxidation of lipids, proteins and DNA and RNA nucleic acids and because of the impairment of glucose metabolism, the free oxygen species [(superoxide (O2•−), hydroxyl (OH•), hydroperoxyl (HO₂•), peroxyl (ROO•), lipid peroxyl (LOO•), alkoxyl (RO•), nitric oxide (NO•)] generation causes the beginning of the inflammatory processes [9]. The observed dysfunction of cell membranes and the increased activation of programmed nerve cell death (apoptosis) are also results from the oxydative stress [10].

In the neuropathology of Alzheimer's disease the important markers of oxidative stress in the brain include [11]:

1. lipid peroxidation products: acrolein, peroxynitrite, 4-hydroxy-2-nonenal, hydroxyoctadecadienoic acid [9];
2. oxidized proteins and nucleic acids: nuclear DNA, mitochondrial DNA and ribosomal RNA;
3. elevated levels of g-glutamyltransferase and of inflammatory factors: microglial Interleukin-1β, Interleukin--6, tumor necrosii factor (TNFα), reactive C-protein and α1-antichymotrypsin, synthesized in astrocytes;
4. glycosylation products [9];
5. decreased concentration of the Aβ-peptide-destruction enzyme sortryline 1.

Free radicals generate acroleine by oxidation of membrane unsaturated fatty acids [9]. It has been reported that lipid peroxidation leads to the formation of:

1. reactive acrolein, that by interacting with the proteins, forms carbonyl derivatives;
2. 4-hydroxy-2-nonenal, that stimulates the aggregation of Aβ-peptides via covalent attachment and induces neuronal apoptosis by attacking of the phospholipid bilayer membrane;
3. products that by disrupting the function of mitochondrial enzymes, increase the levels of free hydroxyl radicals, that oxidize cellular proteins, lipids and nucleic acids and form dityrosine-linked Aβ-peptides with high affinity to oligomerization and aggregation [10].

By oxidation, the toxic soluble Aβ_1-42 oligomers are converted into aggregates in senile plaques and cause oxidative modification, denaturation and inactivation of cellular proteins. Aggregates of Aβ₄₂-oligomers lead to the following cascade of pathological neurodegenerative changes [2]:

1. neurotransmitter disorders;
2. neuroinflammatory processes;
3. neuroimmune dysfunction;
4. damage of axones;
5. dysfunction of synapses and dendrites;
6. loss of synapses, dendrites and axones;
7. increased levels of superoxide radicals;
8. oxidation of proteins and DNA [9];
9. mitochondrial dysfunction;
10. microglial proliferation;
11. disruption of phospholipid bilayer;
12. amyloid angiopathy;
13. neuronal apoptosis.

This cascade of processes in brain, resultng by the influence of the increased oxidative stress, causes the cognitive degeneration, that further leads to the progression of Alzheimer’s disease in the frontal cortex. Under the influence of oxidative stress, Aβ-aggregates elicit mitochondrial dysfunction, that by initiating of free radical formation, stimulates the oxidation of DNA, resulting in a change in the structure and function of synapses [2].

Factors stimulating tau-protein hyperphosphorylation and formation of neurofibrillary tangles [2] incluse:

1. 1. increased production of Aβ-peptides;
   2. mitochondrial oxidative stress;
   3. reduced activity of antioxidant systems;
   4. enhancement of inflammatory processes.

Currently one of the most promising trend is the use of non-toxic high-effective antioxidants. For the achievement of  this aim two basic strategies can be implemented. One trend is the combination in one product of different functional components that can independently interact synergistically at different stages of the complex multi-stage lipid oxidation process. Other approach is the investigation of high effective, non-toxic and biologically active antioxidants. For the increase of antioxidant and biological activity, it is important to consider not only individual compounds, but also suitable antioxidant compositions, including extracts of natural products containing a very wide range of polyphenol antioxidants with synergistic effect. Plant-based dietary supplements containing antioxidants are important for prevention and treatment of age-related diseases [12].

 

Natural phytocompounds with antioxidant properties against Alzheimer's disease

One of the most promising approach for the prevention of Alzheimer's disease is an antioxidant therapy, that inhibits harmful free radical action by induction of endogenous antioxidant enzymes [13]. The natural phytocompounds [14] with antioxidant properties are new alternatives [15].

Antioxidants as nutritional supplements, improve thinking, memory and mental abilities. Food supplements with antioxidant activity include plant extracts containing flavonoids, polyphenols [16], phenolcarboxylic acids, aminoacids and vitamins.

 

Polyphenols

Polyphenols are natural antioxidants [16] and are classified as: flavonoids [17]: flavonols, flavones, flavanones, flavanols, isoflavones, chalcones, and anthocyanidins [18] (Figure 1) and non-flavonoids: phenolic acids, stilbenes and lignans [19].

Polyphenols posesses antioxidant, antiinflammatory and antiamyloidogenic functions [20].

 

Figure 1. Chemical structures of flavonoids with antioxidant activity.

• Quercetin

Quercetin exerts antioxidant properties. The compound is an aglycone of flavonoid glycosides rutin and quercitrin, Quercetin is found in apples and citrus fruit [21] and prevents neurons from free radicals and suppresses the oxidative neurons damage, that leads to te development of Alzheimer’s disease [22].

• Epigallocatechin-3-gallate

Flavanol Epigallocatechin-3-gallate is found in Camelia sinensis (L.) Kuntze. Because to its antioxidant properties, this phytoconpound suppresses cognitive impairment by reduction of the amyloid-induced mitochondrial dysfunction and neurotoxicity [23].

• Moringine

Isothyocyanate Moringine is isolated from Moringa oleifera Lam. (Moringaceae). This tropical plant is widely used in traditional medicines and as a food supplement. It is characterized by the presence of flavonoids, isothiocyanates, lignans and phenolic acids [24].

Moringine is sulfur-containing phytochemical with a protective effect on neurodegenerative diseases, because of antioxidant and antiinflammatory properties. Other biological activities of Moringine are antimicrobial, antifungal and antiviral [24].

• Magnolol

Magnolia officinalis Rehder & E.H.Wilson (Magnoliaceae) contains biphenolic lignans Magnolol and Honokiol, that  exert neuroprotective effect against Alzheimer’s disease by inhibition of reactive oxygen species. This process include mechanism, such as depletion of Glutatione inhibition of NADPH oxydase activation. The compounds protect nerve cell by suppression of neurotoxicity and by regulation of neuronal function. Magnolol has neuroprotective properties in cortical neuron-astrocyte cultures and protects against Aβ damage [25].

• Honokiol

Honokiol is isolated from Magnolia officinalis Rehder & E.H.Wilson (Magnoliaceae), Japan species Magnolia grandiflora L. and endemic species in Mexico Magnolia dealbata Zucc [25]. Honokiol is known to exert anxiolytic, analgesic, antidepressant, anti-tumorigenic, and neuroprotective properties in cortical neurons. It has been observed that Honokiol protects neurons against Aβ damage. The compound is reported to inhibit the reactive free radicals by improving mitochondrial function  [25].

• Hesperidin

Hesperidin is a flavanone glycoside of aglycon hesperitin, and is found in Citrus aurantium L., Citrus sinensis L. (Osbeck).

The mechanisms of Hesperidin for the improvement of learning. memory and cognition are result of:

1. 1. increasing the anti-oxidative defense systems;
   2. correction of Aβ-induced mitochondrial abnormalities;
   3. restoring of Glutation concentration;
   4. normalization of the mitochondrial enzyme activities;
   5. decreasing of Glycogen synthase kinase-3β, which deactivation can supprees the oxidative damage;
   6. blockage of β- and γ-secretases;
   7. suppression of Aβ_1–40 formation [26].

Extracts of Ginkgo biloba L. leaves contain flavonoids kaempferol, isorhamnetin, myricetin (Figure 2), which protect neurons against oxidative stress.

• Kaempferol

Kaempferol (3,4′,5,7-tetrahydroxy-flavone) is a natural flavonol, which can be found in Hypericum perforatum L., Moringa oleifera oleifera Lam., Rosmarinus officinalis L. [27].

• Myricetin

Myricetin (3,3’,4’,5,5’,7-hexahyfroxyflavone) is found in Citrus aurantium L., Fragaria vesca L, Rubus idaeus. tea [28].

It has been described that mechanisms of neuroprotective effect of this polyphenol compound include:

1. 1. scavenging of free oxygen species;
   2. chelation of transition metal ions that produce free radicals; 
   3. increasing the effects of other antioxidants;
   4. induction of the activity of enzyme glutathione S-transferase, which can protect cells towards free-radicals [28].

 

• Ginkgolide B

In Alzheimer's disease for reduction of oxidative stress are used natural antioxidants from Gingko billoba L. (Ginkgolide B) that reveals neuroprotective potential by the inhibition of amyloid-beta aggregation [29].

Figure 2 illustrates the chemical structures of antioxidant flavonoids Kaempferol, Isorhamnetin and Myricetin.  

 

Figure 2. Chemical structures of antioxidant flavonoids   Kaempferol, Isorhamnetin, Myricetin.

 

Non-flavonoids with antioxidant activity

Non-flavonoids with antioxidant activity and benefits against Alzheimer's disease are Curcumine, Resveratrol, Caffeic acid, Ferulic acid and Rosmarinic acid (Figure 3).

 

Figure 3. Chemical structures of non-flavonoids with antioxidant activity.

 

• Curcumine

Curcumine is a non-flavonoid compound isolated from Curcuma longa L., that protects neurons against oxidative stress. It exerts a benefitial effect in Alzheimer's disease [30] due to antioxidant action, antiinflammatory effect and binding of redox-active metals iron and copper. The compound induces the antioxidant protective system glutathione transferase, lowers cholesterol levels, and binds ferric ions to complexes. Curcumine inhibits the aggregation and formation of Aβ42 oligomer and antiamyloid effects are the result of the increase in enzymes required for amyloid plaque degradation: insulin degradation enzyme and Neprilisine [21].

• Resveratrol

The very important natural polyphenol with a stilbene structure is Resveratrol (3,5,4′-trihydroxystilbene). It belongs to non-flavonoid class polyphenol compounds: stilbenes. Source of Resveratrol are Arachis hypogaea L., Fragaria ananassa Duchesne ex Rozier (Rosaceae), Lycium chilense Bertero (Solanaceae), roots of Polygonum cuspidatum Siebold and Zucc., Rubus idaeus L. (Rosaceae), leaves of Veratrum grandiflorum (Maxim. ex Miq.) O. Loes, roots and rhizomes of Veratrum formosanum O. Loes, Helichrysum spp. (Compositae), Vaccinium spp. (Ericaceae) [21].

The antioxidant properties of Resveratrol are related to its ability:

1. 1. for stimulation of the endogenous antioxidant enzymes superoxide dismutase and catalase;
   2. for reduction the ettect of malondialdehyde in the brain in models of Alzheimer's disease in mice.

Throught these mechanisms the compound acts neuroprotectively and reduces cognitive impairment. Resveratrol possesses anti-Aβ deposition action [31].

• Caffeic acid

The potentiral mechanisms of neuroprotective activity in Alzheimer’s disease of antioxidant Caffeic acid include:

1. normalization of superoxide dismutase activity and glutathione concentration;
2. suppression glycogen synthase kinase 3β  activity;
3. decreasing the level of β-amyloid and phosphorylated tau protein [32].

 

• Ferulic acid

Ferulic acid is a hydroxycinnamic acid, phenol derivative with  antioxidant, neuroprotective, anti-Aβ aggregation, and anti-inflammatory effect [33].

• Rosmarinic acid

Rosmarinic acid is a natural polyphenol antioxidant. trat first was extracted found in Rosmarinus officinalis L. in 1958. It is found in about 160 plants, such as Melissa officinalis  L., Mentha arvensis L., Ocimum basilicum L., Ocimum tenuiflorum L., Origanum majorana L., Origanum vulgare L., Perilla frutescent (L.) Britton, Rosmarinus officinalis L., Salvia officinalis L., Salvia lavandulifolia Vahl. Rosmarinic acid has powerful antioxidant and anti-inflammatory properties and reduces markers of oxidative stress while increasing levels of antioxidant enzymes. Rosmarinic acid can be beneficial in protection of cognitive deficits and may improve learning and memory [34].

 

Alkaloids with antioxidant activity

Plant derived alkaloids which exerts antioxidant activity [35],  show a tendency for efficacy in the treatment of behavioral symptoms, with proven neuroprotective properties against Alzheimer's disease [36]. The more important antioxidant alkaloids wih potential benefit against Alzheimer's disease are: Arecoline (Areca catechu L. ); Galantamine (Galanthus caucasicus (Baker) Grossh., Galanthus nivalis L., Galanthus woronowii Losinsk, Leucojum aestivum L., Narcissus tazetta L.); Nicotine; Morphine, Caffeine (Coffea arabica L,), Berberine (Berberis aquifolium Pursh, Berberis vulgaris L., Coptis chinensis Franch, Hydrastis Canadensis L.), Huperzine  A (Huperzia serrata (Thumb. ex Murray) Trevis., Piperine (Piper longum L., Piper nigrum L.) [21, 35, 36] (Figure 4).

 

Figure 4. Chemical structures of alkaloids with  antioxidant activity.

 

• Nicotine

Nicotine increases the expression of α7-nicotinic receptors and potentiates the cholinergic system, which causes a neuroprotective effect against amyloid toxicity [21].

• Morphine

Morphine from Papaver somniferum L. possesses  an anti-amyloid effect by stimulating the release of estradiol from neurons [21].

• Caffeine

Caffeine is a xanthine alkaloid isolated from Coffea arabica L. In Alzheimer's models, Caffeine exhibits anti-oxidative effect, reduces the tau-proteine phosphorylation [37], decreases the β-amyloid levels in the hippocampus and induces inhibition of lipid peroxidation [21].

• Berberine

Berberine is isoquinoline alkaloid [38] found in Berberis aquifolium Pursh, Berberis vulgaris L., Coptis chinensis Franch, Hydrastis canadensis L. [21].

It has beeu reported that mechanisms of action of Berberine include:

1. 1. exhibits antioxidant activity by increasing d superoxyd dismutase [38];
   2. increases cholinergic transmission by inhibition of butyryl-cholinesterase [39];
   3. stimulates α-secretase activity;
   4. suppresses β- and γ-secretase [40];
   5. blocks tau-proteine hyperphosphorylation [39].

 

• Huperzine A

Alkaloid Huperzine A is isolated from Huperzia serrata (Thumb. ex Murray) Trevis. The compound was approved in China for therapy of Alzheimer's disease in 1994, due to possesses neuroprotective effects by [41]:

1. increasing the concentration of antioxidant enzymes;
2. decreasing the level of free radicals (antioxidant and antiapoptotic activity);
3. reduction of  the glutamate toxicity;
4. inhibition of acetylcholinesterase;
5. antiamilodogenic effect;
6. modulation of  the amyloid precursor protein processing;
7. protection of mitochondria;
8. antiapoptotic effect.

 

• Harmine

Harmine harmine,harmaline is antioxidant isolated from Peganum harmala L. [35].

• Galantamine

Galantamine is the very important alkaloids for therapy of Alzheimer's disease as a centrally active reversible acetylcholinesterase inhibitor. It is a natural product which exerts beneficial activity, leading to the improvement of behavior and protection of brain functional activities. Galantamine inhibits β-amyloid aggregation. It has been reported that Galantamine enhances dopaminergic neurotransmission and possesses antioxidant [42] and neuroprotective properties by the inhibition of reactive oxygene species. The neuroprotective activity of Galantamine against oxidative stress, is mediated through positive allosteric modulatory stimulation of α7-subtype sites-binding [43].

 

Medicinal plants containing compounds with antioxidant activity against Alzheimer disease

For the prevention of oxidative stress an important approach is the investigation and application of plants against Alzheimer's disease [44].

 The effect of plant extracts on aging and Alzheimer's disease has been investigated, and the results showed that higher antioxidant intake improves cognitive function and reduces the risk of development of the disease [7]. The mechanisms of these effects are associated with increased neural communication and decreased oxidative stress [45].

For Alzheimer's disease due to the content of different compounds, very promising antioxidant effect  exhibit the extracts from the different medicinal plants (Figures 5 and 6) such as: Acorus calamus  L., Angelica sinensis L., Asparagus racemosus L., Azima tetracantha Lam, Berberis aquifolium Pursh, Berberis vulgaris L., Camelia sinensis (L.) Kuntze, Centella asiatica L., Citrus aurantium L., Coffea arabica L., Convolvulus pluricaulis Choisy, Coptis chinensis Franch, Curcuma longa L., Daucus carota L., Eryngium campestre L., Eryngium planum L., Galanthus caucasicus (Baker) Grossh. Galanthus nivalis L., Galanthus woronowii Losinsk, Huperzia serrata  (Thumb. ex Murray) Trevis., Glycyrrhiza glabra L.  Hydrastis canadensis L., Juglans regia L., Lavandula angustifolia Mill, Leucojum aestivum L., Lycoris radiata (L’Her.) Herb, Narcissus tazetta L., Morus alba L., Panax notoginseng (Butkill) F.H.Chen, Phyllanthus emblica L., Piper longum L., Piper nigrum L.,Vitis vinifera L., Zingiber officinalis L.) [21, 35, 36, 46].

Some of plants containing the more important  phytocompounds with antioxydant  activity include  [21, 46]:

1. Acorus calamus Linn. (Α-Asarone and Β-Asarone);
2. Angelica sinensis (Oliv.) Diels (Ferulic acid);
3. Berberis aquifolium Pursh, Berberis vulgaris L., Coptis chinensis Franch, Hydrastis canadensis L. (Berberine);
4. Camelia sinensis (L.) Kuntze (Epicatechin, Epicatechingallate, Epigallocatechin, Epigallocatechin gallate, Catechin, Catechingallate, Gallocatechin, Gallocatechingallate, Quercetin, Kaempferol, Myricetin Caffeine, Theophylline, Theobromine [47]
5. Citrus aurantium L. (Nobiletin);
6. Coffea arabica L. (Caffeine);
7. Curcuma longa L. (Curcumin);
8. Galanthus caucasicus (Baker) Grossh., Galanthus nivalis L,, Galanthus woronowii Losinsk, Leucojum aestivum L., Lycoris radiata, Narcissus tazetta L.) (Galantamine)
9. Ginkgo biloba L. (Ginkgolide B, Kaempferol, Isorhamnetin, Myricetin)
10. Huperzia serrata  (Thumb. ex Murray) Trevis, (Huperzine A) [41];
11. Hypericum perforatum L.,  Moringa oleifera Lam., Rosmarinus officinalis L. (Kaempferol)
12. Magnolia officinalis Rehder and E.H.Wilson (Magnolol, Honokiol) [25];
13. Magnolia dealbata Zucc., Magnolia grandiflora L, (Honokiol) [25];
14. Melissa officinalis L. (Caffeic acid [32], Ferulic acid [33];
15. Melissa officinalis  L., Mentha arvensis L., Ocimum basilicum L., Ocimum tenuiflorum L., Origanum majorana L,, Origanum vulgare L., Perilla frutescent (L.) Britton, Rosmarinus officinalis L., Salvia officinalis L., Salvia lavandulifolia Vahl. (Rosmarinic acid) [34];
16. Moringa oleifera Lam. (Moringine);
17. Morus alba L.(Quercetin);
18. Piper longum L., Piper nigrum L. (Piperine) [36]
19. Rosmarinus officinalis L. (Carnosic acid [32], Ferulic acid [33], Hesperidin [26], Rosmarinic acid [34];
20. Arachis hypogaea L., Fragaria ananassa Duchesne ex Rozier, Lycium chilense Bertero, Polygonum cuspidatum Siebold and Zucc. Rubus idaeus L., Veratrum grandiflorum (Maxim. ex Miq.) O.Loes, Veratrum formosanum O. Loes, Vitis vinifera L. (Resveratrol) [36].

Protective antioxidant effect in Alzheimer's disease is caused by extracts of the following different parts of plants [46]:

1. leaves of: Azima tetracantha Lam., Camellia sinensis (L.) Kuntze, Centella asiatica L., Coptis chinensis Franch, Hypericum perforatum L., Melissa officinalis L., Ocimum basilicum L., Ocimum sanctum, Rosmarinus officinalis L., Salvia officinalis L.;
2. seeds and fruits from Ginkgo biloba L., Juglans regia L.;
3. fruits of Phyllanthus emblica L.;
4. roots of Angelica sinensis L., Asparagus racemosus L., Glycyrrhiza glabra L., Withania  somnifera (L.) Dunal.  Panax notoginseng (Butkill) F.H.Chen. [47];
5. rhizomes from: Acorus calamus L., Zingiber officinalis L. [47]
6. roots and rhizomes from: Acorus calamus L.

Some of the more important mechanism of neuroprotective action of natural compound are [47]:

1. antioxidant activity;
2. stimulation of the activity of superoxide dismutase, catalase and glutathione peroxidase: Withania  somnifera (L.) Dunal;
3. improvement of memory and learning due to inhibition of  amyloid beta-peptide 1-42) deposition: Angelica sinensis, Convolvulus pluricaulis Choisy, Ginkgo biloba L., Morus alba L., Hypericum perforatum L, Centella asiatica L. [46];
4. protection against lipid peroxidation) Lavandula angustifolia.

Morinda citrifolia L. (Rubiaceae) is spread in tropical countries such as Australia, Caribbean, Cuba, Dominican Republic, India, Jamaica, Malaysia, Puerto Rico [48].

It has been reported that the extracts of Morinda citrifolia L. fruit  inhibits lipid oxidation. It has been described that found in Morinda citrifolia L. Proxeronine can be converted in the body by an enzyme proxeronase to the alkaloid Xeronine, that exerts the following effects:

1. modification of the proteins structure;
2. ability for changing the intra- or extracellular accumulated aggregated proteins into their original conformation and for revertimg their normal function [48].

Withania somnifera is named(as Ashwagandha, Indian ginseng and is from Solanaceae. The ability of steroidal lactone Withaferin A  to induce changes in the activity of free-radical binfing scavenging enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase are expressed in the following properties:

1. normalizes the superoxide dismutase   activities. 
2. potential to enhance catalase and glutathione peroxidase activities 
3. root extracts are reported to reduce the lipid peroxidation and to increase the decreased glutathione, superoxide dismutase  and catalase levels [49].

Figures 5  and 6 illustrate some of the more applied plants with antioxidant activity against Alzheimer disease.

 

a)	b)	c)
d)	e)	f)
Figure 5.  Medicinal plants containing compounds with antioxidant activity against Alzheimer disease. a) Areca catechu L. b) Berberis vulgaris L. c) Camelia sinensis L. d) Coffea arabica L. e) Curcuma longa L. f) Huperzia serrata (Thunb. ex Murray) Trevis

 

a)	b)	c)
d)	e)	f)
Figure 6. Medicinal plants containing compounds with antioxidant activity against Alzheimer disease. a) Galanthus nivalis L. b) Galanthus Woronowii Losinsk. c) Ginkgo biloba L. d) Magnolia officinalis Rehder & E.H. Wilson e) Peganum harmals L. f) Withania somnifera (L.) Dunal

Aminoacids with antioxidant activity

Antioxidant effects exhibit the following aminoacids: L-Arginine, L-Histidine, L-Isoleucine L-Serine, L-Tryptophan and L-Tyrosine [50] (Figure 7). Camellia sinenensis (L.) Kuntze contains L-Arginine, L-Serine, L-Tryptophan and L-Tyrosine and in Morinda citrifolia L. is found .L-Isoleucine.

 

Figure 7. Chemical structures of aminoacids with antioxidant activity.

Antioxidant activity exhibit a sulfur amino acids: L-Cysteine, N-Acetylcysteine, L-Methionine, Taurine. N-Acetylcysteine ​​has antioxidant properties that alleviate symptoms of depression, and improves activity of the brain and memory. Contained in garlic extract, S-Alyl-L-Cysteine ​​inhibits pathological cascades associated with synaptic degeneration and neuroinflammation. Taurine is an antioxidant that provides access of magnesium and calcium in brain cells and stimulates nerve cells. Phosphatidylserine exhibits antioxidant activity against lipid peroxidation of the membranes of nerve cells and is particularly effective in combination with omega-3 unsaturated fatty acids. In Alzheimer's model in mice it has been shown that the decreasing of the levels of L-Arginine leads to amyloid deposition, hyperphosphorylation of tau-proteine, changes in behavior and loss of neurons. Treatment with L-Arginine improves cognitive function by reduction of oxidative stress [50].

Conclusion

The therapeutic approaches in Alzheimer's disease are connected with improvement of neuronal degeneration. Application of antioxidans, which inhibit free radicals effect  and induce the activity of endogenous antioxidant enzymes, is one of the most promising approach for prevention of Alzheimer’s disease. New perspective for the improvement of cognitive functions is the investigation of natural phytocompounds that  exert synergistic antioxidant effects. For Alzheimer's disease due to the content of different compounds, very promising antioxidant effect exert the extracts from  different medicinal plants. The more important antioxidant compounds with potential benefit against Alzheimer's disease  include: 1) flavonoids Quercetin, Epigallocatechin-3-gallate, Moringine, Magnolol, Honokiol, Kaempferol, Isorhamnetin, Myricetin; 2)  non-flavonoids: Curcumine, Resveratrol, Rosmarinic acid. 3) alkalolids: Arecoline, Berberine, Caffeine, Galantamine, Huperzine  A, Nicotine; Morphine, Piperine. Antioxidant effects exhibit L-Arginine, L-Histidine, L-Isoleucine, L-Serine, L-Tryptophan. L-Tyrosine, L-Cysteine, L-Methionine.

Acknowledgments: None

Conflict of interest: None

Financial support: None

Ethics statement: None

References

1. Losada-Barreiro S, Bravo-Díaz C. Free radicals and polyphenols: The redox chemistry of neurodegenerative diseases. Eur J Med Chem. 2017;133(1):379-402. doi:10.1016/j.ejmech.2017.03.061
2. Beera AM, Seethamraju SM, Nori LP. Alzheimer’s disease: Perspective on therapeutic options and recent hallmarks in clinical research. Int J Pharm Res Allied Sci. 2021;10(4):110-20. doi:10.51847/ViC6sAGCyq
3. Mosaad M, Aljahdali AF. The role of unflammation in early and late phase of Parkinson disease. Pharmacophore. 2021;12(1):51-6.
4. Pedachenko Y, Gridina N, Rozumenko V, Samoylov A, Khrystosenko R, Zvyagintseva T, et al. Changes in the Correlation between peripheral blood cells and membrane charge in brain gliomas and meningiomas. Arch Pharm Pract. 2022;13(3):92-7. doi:10.51847/HfbILJutsJ
5. Firuzi O, Spadaro A, Spadaro C, Riccieri V, Petrucci R,  Marrosu G, et al. Protein oxidation markers in the serum and synovial fluid of psoriatic arthritis patients. J Clin Lab Anal. 2008;22(3):210-5. doi:10.1002/jcla.20243
6. Aldosari MB, Alharbi AA, Alharbi KAT, Almutairi IM, Alharbi MNBM, Altulaihi MAA, et al. Evaluation of the role of angiography in diagnosis and management of brain aneurysm: Literature review. Int J Pharm Res Allied Sci. 2021;10(1):38-41. doi:10.51847/yGJr_Ra
7. Kartashev VP, Xingyuan S, Medvedev IN, Tkacheva ES, Vorobyeva NV. Physiological changes in the erythrocytes of an aging organism experiencing physical. J Biochem Technol. 2023;14(1):50-6.  doi:10.51847/GGLSMMHC5s
8. Mikhaylova IV, Medvedev IN, Makurina ON, Bakulina ED, Ereshko NY, Eremin MV. The effect of playing chess on an aging or pathological organism. J Biochem Technol. 2021;12(3):47-52. doi:10.51847/CwcjG5IstX
9. Markesbery WR, Lovell MA. Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment. Arch Neurol. 2007;64(7):954-6. doi:10.1001/archneur.64.7.954
10. Axelsen PH, Komatsu H, Murray IVJ. Oxidative stress and cell membranes in the pathogenesis of Alzheimer's disease. Physiol. 2011;26(1):54-69. doi:10.1152/physiol. 00024.2010
11. Mangialasche F, Polidori MC, Monastero R, Ercolani S, Camarda C, Cecchetti R, et al. Biomarkers of oxidative and nitrosative damage in Alzheimer’s disease and mild cognitive impairment. Aging Res Rev. 2009;8(4):285-305. doi:10.1016/j.arr.2009.04.002
12. Sergun V, Gorbushina I, Valentina B, Poznyakovsky V, Tokhiriyon B, Lapina V. Plant-based dietary supplements and antler products for prevention and treatment of age-related diseases: Efficacy study. Int J Pharm Res Allied Sci. 2022;11(3):18-25.
13. Anand R, Kiran DG, Mahdi AA. Therapeutics of Alzheimer's disease: Past, present and future. Neuropharmacol. 2014;76(Part A):27-50. doi:10.1016/j.neuropharm. 2013.07.004
14. Ng YP, Or TCT, Ip NY. Plant alkaloids as drug leads for Alzheimer’s disease. Neurochem Int. 2015;89:260-70.  doi:10.1016/j.neuint.2015.07.018
15. Kim MH, Kim SH, Yang WM. Mechanisms of action of phytochemicals from medicinal herbs in the treatment of Alzheimer’s disease. Planta Med. 2014;80(15):1249-58. doi:10.1055/s-0034-1383038
16. Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients. 2010;2(12):1231-46. doi:10.3390/nu2121231
17. Terao J. Dietary flavonoids as antioxidants. Forum Nutr. 2009;61:87-94. doi:10.1159/000212741
18. Dai J, Mumper RJ. Plant phenolics: Extraction, analysis and their antioxidant and anticancer properties. Molecules. 2010;15(10):7313-52. doi:10.3390/molecules15107313
19. Vauzour D. Effect of flavonoids on learning, memory and neurocognitive performance: Relevance and potential implications for Alzheimer’s disease pathophysiology. J Sci Food Agric. 2014;94(6):1042-56.  doi:10.1002/jsfa.6473
20. Ngoungoure VLN, Schluesener J, Moundipa PF, Schluesener H. Natural polyphenols binding to amyloid: A broad class of compounds to treat different human amyloid diseases. Mol Nutr Food Res. 2015;59(1):8-20.  doi:10.1002/mnfr.201400290
21. D’Onofrio G, Sancarlo D, Ruan Q, Yu Z, Panza F, Daniele A, et al. Phytochemicals in the treatment of Alzheimer’s disease: A systematic review. Curr Drug Targets. 2017;18(13):1487-98. doi:10.2174/ 1389450117666161102121553
22. David AVA, Arulmoli R, Parasuraman S. Overviews of biological importance of Quercetin: A bioactive flavonoid. Pharmacogn Rev. 2016;10(20):84-9. doi:10.4103/ 0973-7847.194044
23. Vishnoi H, Bodla RB, Kant R. Green tea (Camellia sinensis) and its antioxidant property: A review. Int J Pharm Sci Res. 2018;9(5):1723-36. doi:10.13040/IJPSR.0975-8232.9(5).1723-36
24. Galuppo M, Giacoppo S, de Nicola GR, Iori R, Navarra M, Lombardo GE, et al. Antiinflammatory activity of Glucomoringin isothiocyanate in a mouse model of experimental autoimmune encephalomyelitis. Fitoterapia. 2014;95(1):160-74. doi:10.1016/j.fitote.2014.03.018
25. Zhu S, Liu F, Zhang R, Xiong Z, Zhang Q, Hao L, et al.  Neuroprotective potency of neolignans in Magnolia officinalis cortex against brain disorders. Front Pharmacol. 2022;13:857449. doi:10.3389/fphar.2022.857449
26. Hajialyani M, Farzaei MH, Echeverría J, Nabavi SM, Uriarte E, Sobarzo-Sánchez E. Hesperidin as a neuroprotective agent: A review of animal and clinical evidence. Molecules. 2019;24(3):648. doi:10.3390/molecules24030648
27. Holland TM, Agarwal P, Wang Y, Leurgans SE, Bennett DA, Booth SL, et al. Dietary flavonols and risk of Alzheimer dementia. Neurol. 2020;94(16):1749-56. doi:10.1212/ WNL.0000000000008981
28. Semwal DK, Semwal RB, Combrinck S, Viljoen A. Myricetin: A dietary molecule with diverse biological activities. Nutrients. 2016;8(2):90. doi:10.3390/ nu8020090
29. Luo Y, Smith JV, Paramasivam V, Burdick A, Curry KJ, Buford JP, et al. Inhibition of 181 amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci USA. 2002;99(19):12197-202. doi:10.1073/pnas.182425199
30. Chin D, Huebbe P, Pallauf K, Rimbach G. Neuroprotective properties of Curcumine in Alzheimer’s disease:  Merits and limitations. Curr Med Chem. 2013;20(32):3955-85. doi:10.2174/09298673113209990210
31. Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for Alzheimer’s disease. Curr Pharm Des. 2012;18(1):27-33. doi:10.2174/ 138161212798919075
32. Pavlíková N. Caffeic acid and diseases - mechanisms of action. Int J Mol Sci. 2023;24(1):588. doi:10.3390/ijms24010588
33. Singh YP, Rai H, Singh G, Singh  GK, Mishra S,  Kumar S, et al. A review on Ferulic acid and analogs based scaffolds for the management of Alzheimer’s disease. Eur J Med Chem. 2021;215:113278. doi:10.1016/j.ejmech.2021.113278
34. Hase T, Shishido S, Yamamoto S, Yamashita R,  Nukima H, Taira S, et al. Rosmarinic acid suppresses Alzheimer's disease development by reducing amyloid β aggregation by increasing monoamine secretion. Sci Rep. 2019;9(1):8711. doi:10.1038/s41598-019-45168-1
35. Sirin S, Dolanbay SN, Aslim B. Role of plant derived alkaloids as antioxidant agents for neurodegenerative diseases. Health Sci Rev. 2023;6:100071. doi:10.1016/j.hsr.2022. 100071
36. Hussain G, Rasul A, Anwar H, Aziz N, Razzaq A, Wei W, et al. Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int J Biol Sci. 2018;14(3):341-57. doi:10.7150/ijbs.23247
37. Laurent C, Eddarkaoui S, Derisbourg M, Leboucher A, Demeyer D, Carrier S, et al. Beneficial effects of Caffeine in a transge-nic model of Alzheimer’s disease-like tau pathology. Neurobiol Aging. 2014;35(9):2079-90. doi:10.1016/j.neurobiolaging.2014.03.027
38. Nagarajan S. A review of potential hepatoprotective compounds from medicinal plants. Pharmacophore. 2022;13(4):8-22. doi:10.51847/9jMktTwwjl
39. Huang M, Chen S, Liang Y, Guo Y. The role of Berberine in the multi-target treatment of senile dementia. Curr Top Med Chem. 2016;16(8):867-73. doi:10.2174/ 1568026615666150827095433
40. Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, et al. Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Abeta secretion. Biochem Biophys Res Commun. 2007;352(2):498-502. doi:10.1016/j.bbrc.2006.11.043
41. Xing SH, Zhu CX, Zhang R, An L. Huperzine a in the treatment of Alzheimer’s disease and vascular dementia: A meta-analysis. Evid Based Compl Altern Med. 2014;2014(1):363985. doi:10.1155/2014/363985
42. Tsvetkova D, Obreshkova D, Zheleva-Dimitrova D, Saso L. Antioxidant activity of Galanthamine and some of its derivatives. Curr Med Chem. 2013;20(36):4595-608. doi:10.2174/09298673113209990148
43. Traykova M, Traykov T, Hadjimitova V, Krikorian K, Bojadgieva N. Antioxidant properties of Galantamine hydrobromide. Z Naturforsch C. 2003;58(5-6):361-5. doi:10.1515/znc-2003-5-613
44. Obulesu M, Rao DM. Effect of plant extracts on Alzheimer's disease: An insight into therapeutic avenues. J Neurosci Rural Pract. 2011;2(1):56-61. doi:10.4103/0976-3147.80102
45. Howes MJR, Perry NSL, Hougthon PJ. Plants with  traditional uses and activities, relevarnt to  the manatgement of    Alzheimer's disease and other cognitive disorders. Phytother  Res. 2003;1:1-18. doi:10.1002/ptr.1280
46. Pratap GK, Ashwini S, Shantaram M. Alzheimer's disease: A challenge in managing with certain  medicinal plants. Int J Pharm Sci Res. 2017;4(8):4960-72. doi:10.13040/ IJPSR.0975-8232.8(12).4960-72
47. Wąsik A, Antkiewicz-Michaluk L. The mechanism of neuroprotective action of natural compounds. Pharmacol Rep. 2017;69(5):851-60.  doi:10.1016/j.pharep.2017.03.018
48. Singh H, Banerjee S, Karan S, Das B, Naskar D, Chatterjee TK. Pharmacological overview of freeze dried Andaman noni (Morinda citrifolia L.) against cancer and neurological disorder. IJPSR. 2015;6(4):1342-50.
49. John J. Therapeutic potential of Withania somnifera: A report on phyto-pharmacological properties. Int J Pharm Sci Res. 2014;5(6):2131-48. doi:10.13040/IJPSR.0975-8232.5(6).2131-48
50. Piubelli L, Murtas G, Rabattoni V, Pollegioni L. The role of D-amino acids in Alzheimer's disease. J Alzheimers Dis. 2021;80(2):475-92. doi:10.3233/JAD-201217