The ecological role of essential oils and their possible therapeutic activities

Marco Valussi!www.infoerbe.it!

www.marcovalussi.it

Why do plants produce SM?The “received view”: coevolutionary arms-race!

vs.!The screening hypothesis

Used by animal for other purposes

Sm 1

Detox 1

Sm 2

Detox 2

Sm 3

Detox 4

Plant

Animal

Coevolutionary arms-race

!

Problems of the coevolutionary arms-race (CAR) model

•They could be exaptations!

•Too many similar compounds in a plant, most weakly active!

•It is a rare event for a molecule to be pharmacologically active

• It is improbabile for a molecule with low biological activity to be part of the chemicals arms race!

• No organism can retain a molecule which causes a loss without immediate advantages!

• Then why have so many molecules with low biomolecular activity been maintained? 

!

Problems of the CAR model

Firn R.D. and Jones C.G (2003). Natural products a simple model to explain chemical diversity. Natural Products Reports, 20, 382391.!

“Evolution would favor organisms that could generate and retain chemical diversity at low cost. Since the greater the chemical diversity the greater the chance of producing the rare chemical with potent bioactivity, the

organisms better able to produce and retain it will have an increased likelihood of better fitness.”

!

The Screening Hypothesis

The metabolic traits that would help increase generation and retention of chemical diversity:!

• enzymes with a broad substrate tolerance!

• reactions giving branched and shared pathways!

• matrix pathways

!

The Screening Hypothesis

M1

M2

M2’

M3

M3’

M4

M4’

E1

E2 E3

E2

E3 E1

Promiscuous enzymes

M1

M2

M3

M4

E4

E4

E4

Reactions giving multiple products

M1 M2

M1+

M3

M2+

M3+

M4

M6 M6+

M5

M4+ M5+

Matrix metabolic pathways

Owen, S.M. and Penuelas, J. (2005) Opportunistic emissions of volatile isoprenoids. Trends Plant Sci. 10, 420–426!

Volatile isoprenoids synthesis occurred as a fortuitous accident of essential isoprenoid synthesis.

!

The opportunistic theory of terpenoid production

Essential isoprenoids!(high mw)

chlorophyll side chains

Carotenoids

C5Mevalonate and MPE C10 C15 Cn

Non essential, volatile!isoprenoids

Fortuitous emission

Biological effectsNo effects

Etc.

Why are SM useful to humans?Chance or what?

SMs

Human target

Non-human target

Coincidence

Signalling GIT physiology

Evolutionary continuity

Detoxification Adaptive advantage

Signalling Xenohormesis

Plants Metabolic machinery

Single potent

SM

Many weak SMs

SH

CAR

Classical pharmacology,

adaptation, heuristic

Network pharmacology, coincidental

synergy

Are complex mixtures interesting?

And if so, why?

The classical position

MAPs are just vessels for diluted "drugs".!

By "reverse pharmacology" it would then be possible to identify the real active single compound and isolate it.!

The traditional uses are just that, traditional uses that cannot be confirmed.

A new position

MAPs influence physiology and pathology through a mixtures of different compounds and possibly via different modes of action!

Complex mixtures can facilitate synergy, and the SH supports this view. !

The SH however does not imply that plants produce SMs in order to facilitate synergy

Many weak SMs

Synergy

Pharmacodynamic

Inhibition of many steps

Membrane action

Pharmacokinetics Enzymatic

action

Analogies

Network pharmacology

Polypharmacy

Network pharmacology

• Network pharmacology: multiple, low-dose, weak ligands can disrupt a network like a single strong ligand. !

• SH proposes that SMs are in general low potency and low affinity molecules, hence candidates for network pharmacology agents.

Synergy in essential oilsas antimicrobials

Synergy in EOs

• Dearth of data in support of synergy in EOs, mainly in vitro studies. !

• Predictions are complex: minor and major components, their stereochemistry.!

• Cases of antagonism (EO less active than fractions or molecules)

Thymus vulgaris CT thymolThe interactions (FICi) between seven of its compounds (thymol, carvacrol, linalol, p-cymene, borneol, alpha-terpinene, gamma-terpinene) tested at 1:1 were:!

1% antagonistic!

21% synergistic!

42% additive !

36% indifferent. !

Most of the synergistic mixtures were synergistic in all different rations, according to the isobole method

AcrA

Geraniol

Antibiotic

Antibiotic

Enzyme

ATP production

Protein synthesis

Intracellular!protein

p-Cymene

Carvacrol

Carvacrol Eugenol/!cinnamaldehyde

Thymol CarvacrolEugenol

Cinnamaldehyde

Antibiotic

Two intracellular!steps

Anti efflux

Two membrane!steps

Pharmacokinetics

Synergy• Individual potency does not determine the potential of the

combination.!

• Synergy more likely with a strongly active molecule and a weak one: carvacrol+ cymene; eugenol + menthol!

• Additivity more likely with two equally active molecules: carvacrol + thymol!

• The chemical features which make a molecule more antibacterial make it less easy to partition in the membrane!

• The lack of them make it easier to infiltrate the membrane and enlarge it, facilitating the passage of the more active molecule

Interesting synergistic EOs

EO Molecule 1 Molecule 2 Examples

Cinnamomum zeylanicum cortex et fol

cinnamaldheyde eugenol E. coli

Ocimum basilicum CT linalool; CT estragole eugenol linalool E. coli, L. monocytogenes, E. aerogenes

Origanum marjorama CT linalool carvacrol linalool

Origanum vulgare

carvacrol p-cymene E. coli, B. cereus, E. faecalis

thymol/carvacrol p-cymene E. coli, B. cereus, E. faecalis

thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium

Satureja spp. thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium

Thymbra spicata carvacrol p-cymene E. coli, B. cereus, E. faecalis

Thymus serpyllum thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium

Thymus spp. thymol p-cymene

EO Molecule 1 Molecule 2 Examples

Thymus spp. CT borneol thymol carvacrol P. aeruginosa, E. aerogene,s E. coli, L. monocytogenes,

Salmonella thyphimurium

Thymus spp. CT linalool

thymol linalool P. aeruginosa, L. monocytogenes

linalool p-cymene C. tropicalisThymus spp. CT thymol/carvacrol thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,

Salmonella thyphimuriumThymus vulgaris CT carvacrol carvacrol p-cymene E. coli, B. cereus, E. faecalis

Thymus vulgaris CT limonene

thymol/carvacrol linalool P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,

Salmonella thyphimurium

linalool p-cymene C. tropicalisThymus vulgaris CT thymol thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,

Salmonella thyphimuriumThymus x citriodorus carvacrol p-cymene E. coli, B. cereus, E. faecalis

Thymus zygis CT thymol

thymol p-cymene

thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium

Trachyspermum ammi thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium

Conclusions

!

“Strong” coevolutionary hypothesis

Strong heuristic tool: an unknown EO could act via network pharmacology, being in a way designed by evolutionary forces, and being possibly better than any isolated compound

• Synergy is present in EOsbecause of their rich chemical diversity, but this can’t be used as a heuristic tool.  !

• It can be used as an explanation when confronted by an EO which is superior or shows different activities and effectiveness than any isolated molecule

!

“Weak” coevolutionary hypothesis

!

Concluding remarks•It is difficult to give an answer to the main question, but…!

•… experimental data on synergy, network pharmacology, and the complexity of biological systems, point towards the plausibility of a synergistic mechanism in EOs  !

•To maintain that the activities of medicinal plants must be always reduced to the activity of a single molecule is bad science!

•The way forward: delve deeper in the field, invest in more clinical trials

Thank you for your attention.