Download Plant Drugs of the Central Nervous System

Plant Drugs of the Central
Nervous System
Central Nervous System
• The brain and spinal column
• The body’s control
system…also responsible for
sensory perception, thought,
mood, memory, etc.
• synapses within the CNS rely
on a number of different
neurotransmitters
CNS Neurotranmitters
• Catecholamines (norepinephrine, epinephrine,
dopamine)
• Acetylcholine
• Tryptamines (serotonin)
• GABA (= ϒ-aminobutyric acid)
• Endorphins
• Cannabinoids
• Histimine
• Glutamate
• Glycine
Norepinephrine
• primary catecholamine, released from the
adrenal medulla and postganglionic
sympathetic neurons
• removed from synapses through re-uptake
• metabolized in the presynaptic terminal by
endogenous monoamine oxidase (MAO) and
catechol-O-methyltransferase (COMT)
Norepinephrine
• Drugs that increase norepinephrine
concentrations in CNS synapses can be used to
treat depression
• Norepinephrine antagonists can be used to
treat psychosis and mania
Norepinephrine Antagonist: Reserpine
• from Rauvolfia serpentina
• binds storage vesicles in membrane transport
system, causing them to release their
norepinephrine…this results in its destruction
by MAO and the subsequent depletion of
norepinephrine from andrenergic terminals
Norepinephrine Antagonist: Reserpine
• in Ayurvedic medicine, root of Rauvolfia
serpentina used to treat mania and as a
sedative
• in Western medicine, Reserpine is used as a
treatment for hypertension and psychosis
Norepinephrine Enhancer: Cocaine
• from Erythroxylum coca
• blocks nerve terminal
membrane transport
system, preventing reuptake of
norepinephrine (and
other catecholamines)
• results in an
accumulation of
norepinephrine at
receptors
Norepinephrine Enhancer: Hypericum
perforatum
• St. John’s wort
• Originated in Eurasia,
naturalized in North
America
• All plant parts taken to
treat depression
• Clinically demonstrated
efficacy for treatment
of mild to moderate
depression
Norepinephrine Enhancer: Hypericum
perforatum
• mechanism of action
is probably through
inhibition of MAO,
which results in
accumulation of
norepinephrine
• may also inhibit reuptake of serotonin
Norepinephrine Enhancer:
Peganum harmala
Peganum harmala
• Harmal
• Native to eastern Mediterranean
to India
• Seeds traditionally used as an
entheogen (sacred hallucinogen)
and as a source of “Turkish Red”
used in western Asia for dyeing
carpets
• Widely naturalized / weedy in
southwestern US (very drought
tolerant)
Peganum harmala
• One of the active compounds in harmal is
harmaline
• Harmaline is used as a sedative and to treat
depression
• Mechanism of action: Harmaline inhibits MAOA, which leads to an increased availability of
neurotransmitters (norepinephrine, serotonin)
Dopamine
• prominent neurotransmitter in midbrain
neurons
• released from hypothalamus
• metabolized by MAO and COMT
• D1 and D2 receptors use dopamine as signal
• Parkinson’s disease is the result of
degeneration of neurons that use D2
receptors
Dopamine Enhancers
• Levodopa, derived from Mucuna spp. is the
metabolic precursor to dopamine. In the body,
levodopa is decarboxylated to dopamine,
which is then available to the brain
• Bromocriptine and pergolide, chemical
derivatives of the ergot fungus, Clavaceps
purpurea. Both are dopamine receptor
agonists
Dopamine Enhancer: Mucuna spp.
• in pea family, Fabaceae
• in India, seeds taken
orally to lessen
irritability and leaves
taken orally as a nerve
tonic
Dopamine Enhancer: Mucuna spp.
• active compound: L-dopa
(levodopa), metabolic
precursor to dopamine
• in Western medicine,
levodopa used in
treatment of Parkinson’s
disease
– especially good for
akinesia (immobility) and
postural imbalance
Dopamine Enhancer: Claviceps purpurea
• ergot fungus
• origin: Europe
• small parasitic fungus
that attacks rye grain
• historically, people would
eat infected rye and have
vivid hallucinations
because of the similarity
of some of the ergot
alkaloids to LSD
– “St. Anthony’s Fire”
Dopamine Enhancer: Claviceps purpurea
• Chemical derivatives of
ergot alkaloids:
– bromocriptine
– pergolide
• In modern medicine,
used to treat
Parkinson’s disease
Serotonin
• neurotransmitter with high concentrations in
brain
• formed from tryptophan
• converted to melatonin in the pineal gland
• compounds that inhibit the re-uptake of
serotonin at receptors (and hence increase levels
of serotonin in synaptic cleft) are used to treat
depression
– synthetic inhibitor: Prozac
– putative plant serotonin uptake inhibitors: St. John’s
wort, harmal
Hallucinogenic Compounds with Structure
Similar to Serotonin
• LSD (synthetic)
• Harmine from Ayahuasca
(Banisteriopsis caapi)
• Mescaline from peyote
(Lophophora williamsii) and San
Pedro cactus (Echinopsis pachinoi)
• Ergot alkaloids from Claviceps
purpurea
• Psilocin from various mushrooms
(e.g., Psilocybe)
• Morning glories (Turbina
corymbosa and Ipomoea violaceae)
Hallucinogenic compound that blocks CNS
muscarinic receptors in the brain
• Scopolamine from various members of the
Solanaceae
– Atropa belladonna
– Hyoscyamus niger
– Datura spp.
– Brugmansia spp.
GABA (γ-aminobutyric acid)
• major inhibitory neurotransmitter in CNS
• synthesized from glutamate
• GABAa receptor protein is the site of action of
benzodiazepines and barbituates (synthetic
anti-seizure medications and sedatives)
GABA Antagonist: Anamirta cocculus
• fish-berry or Indian berry in
Indomalaysia
• in Indomalaysia, fruit is used
as a fish poison, insecticide,
and treatment for head lice
• active compound: Picrotoxin
• stimulates CNS by inhibiting
action of GABA
• modern therapeutic uses:
– treats barbituate poisoning
– CNS stimulant
– schizophrenia
GABA Enhancer: Areca catechu
• nipecotic acid in Areca
catechu is precursor of
chemical derivative,
gabitril
• Gabitril blocks the reuptake of GABA and
increases its
concentration at
receptors
GABA Enhancer: Areca catechu
• seizures occur when too
many impulses
generated in brain
• since gabitril enhances
GABA levels and GABA
has an inhibitory effect
on neurotransmitters,
gabitril is used to treat
seizures
GABA Enhancer: Piper methysticum
• Kava
• Social beverage, served to
visitors in South Pacific (Fiji,
Vanuatu, Polynesia, Micronesia)
as an indication of hospitality
and friendship
• Consumed during village
meetings to facilitate consensus
decision making,
communication, and harmony
• Kava consumption is of similar
social importance to tea, coffee,
and matte consumption in other
parts of the world
GABA Enhancer: Piper methysticum
• kavain and dihydrokavain are kava lactones
that most easily pass through blood-brain
barrier and enter into brain
• kava lactones appear to enhance GABA levels
in CNS; also inhibit re-uptake of
norepinephrine and act as reversible MAO
inhibitors
• therapeutic uses include:
– anti-anxiety
– sleep enhancer
GABA Enhancer: Valeriana officinalis
• Valerian
• native to Europe
• root traditionally used as
sedative and sleep
enhancer
• active chemicals:
valepotriates, enhance
GABA levels in CNS
• used as a sedative and
sleep enhancer
Other putative GABA Enhancers
• Melissa officinalis (Lemon Balm)
• Humulus lupulus (hops)
• Lavandula augustifolia (lavender)
• All these herbs used in various combinations
(often with valerian) as sedatives, sleep aids
and anti-anxiety treatments
Endorphins
• bind to opiate receptors in brain and have
analgesic (pain reducing) effects
Opiate receptor agonists: Papaver somniferum
• opium, opium poppy
• originated in western
Mediterranean & Near
East
• dried latex from
immature fruit capsules
traditionally used as an
analgesic, inebriant,
hypnotic, and treatment
for diarrhea
Opiate receptor agonists: Papaver somniferum
• opium contains 20 alkaloids,
including:
• morphine ( heroin)
• codeine
• papaverine ( verapamil)
• thebaine ( etorphine HCL)
• noscapine ( narcatine)
Opiate receptor agonists: Papaver somniferum
Therapeutic uses:
• morphine = analgesic
• codeine = analgesic, antitussive
• noscapine (narcotine) =
antitussive
• Mechanism of analgesis:
• stimulation of opiate receptors
inhibits the release of substance
P, the neurotransmitter
responsible for inflammatory
responses and pain
Cannabinoids
• Type-1 cannabinoid receptors (CB1) are found
in CNS
• stimulation of these receptors has analgesic
and anticonvulsant effects as well as
antiemetic/antinausea effects
Cannabinoid receptor agonist: Cannabis sativa
• marijuana
• origin in Asia, now grows
worldwide
• active compounds in
inflorescences and
leaves:
– tetrahydrocannabinol
(THC)
– marinol & dronabinol
Cannabinoid receptor agonist: Cannabis sativa
mechanism of action:
stimulate cannabinoid receptors
in CNS (brain cortex,
hippocampus, striatum and
cerebellum)
therapeutic uses include:
• antinausea
• antiemetic
• analgesic
• glaucoma
• muscle relaxant
• anticonvulsant
Cannabinoid receptor agonists: Theobroma
cacao
• Cacao, chocolate
• contains three
unsaturated Nacylethanolamine
compounds including
anandamide, an
endogenous cannabinoid
in the human CNS
• all three compounds
may act as cannabinoid
mimics
Glutamate
• Naturally occurring salts of glutamic acid (Glu
or E, a non-essential amino acid)
• Most abundant excitory neurotransmitter in
the brain
• Glutamate receptors involved in cognitive
functions like learning and memory
• The synthetic drugs PCP and Ketamine
antagonize glutamate receptors in the brain,
resulting in strong dissociative and
hallucinogenic effects
Glutamate
• Glutamate was discovered
in 1908 by a Japanese
chemist who isolated the
substance (in brown crystal
form) from the seaweed
kombu (Saccarina japonica)
• The brown crystals tasted
great! In this way the
essential taste umami was
discovered
• Soon after, the salt
monosodium glutamate was
synthesized as a flavor
enhancer
General CNS Stimulants
• Caffeine (and other methylxanthines,
theobromine and theophylline) – affect multiple
pathways, including stimulation of
norepinephrine receptors and modulation of
dopamine release. May also affect serotonin
receptors
• most commonly consumed psychoactive
compound
• many plant sources ( methylxanthines act as a
natural deterrent to herbivorous insects)
General CNS Stimulants
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plant sources of methylxanthines include:
Coffea robusta (coffee)
Camellia sinensis (tea)
Theobroma cacao (chocolate)
Cola acuminata (cola nut)
Ilex paraguariensis (mate)
Paullinia cupana (guarana)
Coffea arabica, C. robusta
Camellia sinensis
Theobroma cacao
Cola accuminata
Ilex paraguariensis
Paullinia cupana
CNS Stimulants: Catha edulis
• khat, qat
• cultivated in Ethiopia,
Somalia & Yemen
• fresh leaves chewed
socially as a stimulant
• active compounds are
cathine (dnorisoephedrine) and
cathione
CNS Stimulants: Catha edulis
• appears to slow the reuptake of
norepinephrine, leading
to stimulation of CNS /
wakefulness
• cathione also has a high
affinity for serotonin
receptors, which is
likely responsible for
euphoria produced by
qat use
CNS Protective Plants
• Some plant compounds (particularly
flavonoids) are very affective scavengers of
free-radicals, the major source of oxidative
cellular damage
• Reducing oxidative damage to neurons and
receptors can have a positive affect on
cognition and general neurological health
Ginkgo biloba
CNS Protective Plants
• Ginkgo biloba
• Flavoloids (ginkgo flavone glycosides) the
principle active ingredient in Ginkgo preparations
• These flavonoids are responsible for the freeradical scavenging anti-oxidant effects of Ginkgo
• Ginkgo’s neuroprotective properties attributed to
anti-oxidant inhibition of age-related decline of
adrenergic and cholinergic receptors
CNS Protective Plants
• Ginkgo has also been
shown to be effective
in inhibiting the
progression of
Alzheimer’s disease,
presumably also
through reduction of
oxidative cellular
damage
Aspalathus linearis
Aspalathus linearis
• Rooibos, Redbush tea
• Fabaceae (pea family)
• Native to Fynbos of
South African Cape
• Dried leaves are
prepared as a tea
(either fermented or
green)
CNS Protective Plants
• Rooibos tea has been shown
to have protective effects
against oxidative damage to
the CNS
• In one study, rooibos tea
administration prevented
age-related accumulation of
lipid peroxides in several
regions of rat brain, and led
to retention of brain
signaling compared to the
control
Cucurma longa
CNS Protective Plants
• Tumeric
• Native to SE Asia, India
• Curcumin, a polyphenol
compound responsible
for the bright yellow
color of turmeric, is
believed to be the
principal
pharmacological agent
CNS Protective Plants
• Beta-Amyloid (betaA)-induced
oxidative stress is a wellestablished pathway of
neuronal cell death in
Alzheimer's disease
• Cucurmin has been shown to
protect neuronal cells from
betaA(1-42) insult, most likely
through antioxidant pathways
• Other animal studies of
Alzheimer's disease also
suggest that curcumin may
reduce levels of amyloid and
oxidized proteins and prevent
cognitive deficits