estrogens are useful in the treatment of Parkinson's disease. the estrogen receptors and the mechanism behind their effect is shown in the ppt.

1. Gonadocorticoids: A Potential Treatment for
Parkinson’s Disease
Application No: 3761e66eed9811e988936d302365408d
Name: Surbhi Panwar
Affiliation: Pursuing M. Pharm, Amity University, Lucknow
Campus, Uttar Pradesh

2. S. no. Topic Slide no.
1. Parkinson’s disease 3
2. Female hormones 5
3. Synthesis and metabolic pathways of
estrogen
6
4. Estrogen receptor mechanism of action 7
5. GPR30 and ERX 8
6. Physiologic effects of estrogen 9
7. Models of Parkinson’s disease 11
8. Neuroprotection by Estrogens 13
9. Measure of toxicity and neuroprotection by
Dopaminergic markers
14
List of contents:
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3. S.no. Topic Slide no.
10. Neuroprotection by Androgens 17
11. Neuroprotection by Progesterone 18
12. Neuroprotection by Estrogen receptors 19
13. Mapk And Pi3k/Akt Signaling Pathways In
Neuroprotection Against MPTP and MA
Toxicity
20
14. Endogenous Estrogen Exposure In PD 21
15. Hormone Therapy In PD 22
16. Contraceptive pills in PD management 23
17. References 25
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4. Parkinson’s Disease
 Originally called as "Shaking Palsy".
 Defined as the brain disorder which involves loss of
dopaminergic cells in the substantia nigra and abnormalities
in the neurons in basal ganglia.
 It is also characterized by the degeneration of other neuronal
groups that are serotonergic neurons, noradrenergic neurons
or cholinergic neurons .
 Since 1970: Levodopa (L-dopa) is used for treatment (most
effective).
 Carbidopa is combined with L-dopa, allowing it to get to the
brain.
 Deep brain stimulation surgery : reduces symptoms of
disease but will not stop Parkinson disease (PD) to progress.
Fig. 1
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5.  According to studies of death rates and prevalence, it is observed that PD is
more common in men with a relative risk of 1.5 times greater than women.
 This suggests that there is a protective effect of gonadocorticoids in the
brain.1
Adrenal gland
Outer cortex Inner medulla
Outermost region Middle region Innermost region
Mineralocorticoids Glucocorticoids Gonadocorticoids
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6. Female Hormones:
 Estrogen (major): comes from ovaries but small amounts are produced in
the adrenal glands and fat cells. During pregnancy, the placenta also makes
estrogen.
 Progesterone: produced by the ovaries after ovulation.
 Hormonal imbalance in the female body can be sign of Polycystic Ovarian
Syndrome (PCOS), Androgen Excess or Hirsutism.
Types:
a. Natural: Estradiol, estrone, estriol
b. Synthetic:
 Steroidal: Ethinyl estradiol, Mestranol,Quinestrol.
 Non-steroidal: Dienestrol, Diethylstilbestrol, Benzestrol, Hexestrol.2
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7. Pregnenolone Pregnenolone
Synthesis and Metabolic Pathways of Estrogens:
Follicular phase Luteal phase
17-α hydroxypregnenolone Progesterone
Dehydroepiandrosterone 17-α hydroxyprogesterone
Androsenedione Testosterone
Esterone 17-ᵦestradiolEstriol 16-α hydroxyesterone
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8. Estrogen Receptor Mechanism of Action:
1. Both estrogen and SERM bind to ER;
ligand-activated transcription factor;binds
to ERE sequences in target genes in
nucleus and recruite coregulatory proteins
and thus regulates transcription of target
genes.
2. “Nongenomic” effects of estrogen may
occur through binding with the ER
located in or adjacent to the plasma
membrane. Presence of “adaptor”
proteins is required to target the ER to the
membrane and activation of which is
required to bring a rapid change in
cellular signaling molecules along with
stimulation of kinase activity. All this in
turn effects transcription.
3. Intracellular response may also be
triggered by other non-ER membrane-
associated estrogen-binding proteins
(EBPs).
Fig. 2
Signaling cascade
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9. GPR30
•Seven transmembrane domain G-protein
coupled receptor
•Present in plasma membrane,
endoplasmic reticulum and golgi
apparatus of neurons.
•Functions as a membrane estrogen
receptor.
•Mediates both rapid and transcriptional
actions in response to estrogen.
• According to immunohistochemical
studies, a high expression of GPR30 is
observed in hypothalamic- pituitary axis,
hippocampus, and striatum as well as in
substantia nigra.
ER-X
•Plasma membrane associated ER
which is found in the neocortex.
• Activated by endogenous ligand
17α-estradiol and 17β-estradiol and
in turn mediates the activation of
MAPK.3
Fig. 3
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10. Physiologic Effects of Estrogen:
 Female Maturation:
 Stimulates development of uterus, vagina and secondary sexual characteristics.
 Ductal growth of breast and stromal development stimulation.
 Contribution in the development of axillary and pubic hair.
 Stimulate pigmentation of skin particularly the nipples, areolae, and genital region.
 Endometrial effects:
 Growth of the uterine muscles.
 Development of endometrial lining.
 Metabolic effects:
 Maintains normal structure of the skin as well as blood vessels in women.
 Decrease in the rate of bone resorption.
 Alters circulating levels of transcortin, TBG, SHBG, rennin substrate and intestinal
absorption.
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11.  Effects on blood coagulation:
 Levels of factors II, VII, IX, and X increase in circulation and levels antithrombine III
decreases.
 Enhances blood coagulability, increases plasminogen levels and decreases platelet
adhesiveness.
 Other physiologic effects:
 Progesterone receptors synthesis.
 Responsible for estrous behavior in animals and effects lipido in humans.
 Sodium- water retention by kidneys.
 Regulation of control of SM function.2
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12. Models of Parkinson’s Disease:
 In-vivo and in-vitro models helped us to understand that Estradiol hormone
protects against neuronal damage.
 This damage was induced by glutamate excitotoxicity, ᵦ-amyloid peptide, 6-
hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion
(MPP+).
MPTP (1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine) Model:
•MPTP is highly toxic, lipophilic in nature
and selectively damages substantia nigra
DA neurons in humans as well as animals.
•Males are more sensitive to MPTP
treatment with greater neuro toxic effect
than females.
•Reports declare that estrogen shows its
neuroprotective effect in MPTP animal
models.3
How MPTP induces Parkinsonism?
MPTP
BBB
MAO-B
MPP+
Dopaminergic
transporter
MPP+ ROS
Oxidative stress
Lipid peroxidation
Protein peroxidation
DNA damage
Complex I
inhibition
ETC inhibition
Mitochondria
ATP decrease
Cell death
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13. Methamphetamine Model:
Methamphetamine (MA) is a psychostimulant, a potent drug of abuse that causes
degeneration of striatal dopaminergic neurons by long lasting depletion of dopamine
transporter (DAT) in humans and animals.
Male mice are found to be more sensitive to MA induced toxicity.
They show greater reductions in DAT specific binding, striatal DA contents and 3, 4
dihydroxyphenylacetic acid (DOPAC) concentrations whereas in female mice only
lateral part of the striatum was affected.3
Fig.4
1.MA competitively inhibits reuptake of DA by
DAT.
2. MA causes phosphorylation of DAT resulting in
internalization.
3. MA inhibits DA synaptosomal uptake by
VMAT-2.
4. Intracellular uptake of MA causes reverse
transport of DA via DAT synapse.
5. MA diffuses into synaptosomes impairing
storage of DA.
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14. Neuroprotection by Estrogens:
 According to the studies, estrone shows
beneficial action against NMDA,
glutamate, glucose deprivation, H2O2
toxicities and ischemic injury and has
weak neuroprotective activity.
 Estriol shows protection against glucose
deprivation, beta-amyloid peptide, and
NMDA and glutamate toxicities but lacks
neuroprotective activity.
 In-vitro studies report the neuroprotective
effect of 17α- estradiol against MPP+
toxicity is because of its anti-oxidant
activity.
 Whereas, 17α estradiol showed no
protective activity against MPTP- treated
mice.4,5
ESTRADIOL
Prevention of
cell death
Axonal
sprouting
Regeneration
Synaptic
transmission
NEUROPROTECTION
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15. Measure of Toxicity and Neuroprotection by
Dopaminergic Markers:
 DAT (dopamine transporter) is found to be involved in MPTP/MPP+
entry and its accumulation in DA neurons whereas VMAT2 sequesters
MPTP/MPP+.
 High DAT to VMAT2 ratio is associated with greater susceptibility to
neurotoxins.
 In- situ hybridization studies show that in MPTP- treated mice, levels of
DAT mRNA decreases in the substantia nigra but treatment with 17beta-
estradiol completely prevented the reduction of DAT mRNA levels as well
as prevented the decrease in the VMAT2 mRNA levels and tyrosine
hydroxylase mRNA in substantia nigra.
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16. Methamphetamine (MA) targets DAT and enters the cell terminal through it.
After entering the cell terminal, it promotes reverse transport through DAT and
DA is released in the extracellular space.
Accumulation of DA in extra or intra neuronal space induced by MA leads to
formation of ROS which can decrease DAT function.
Also, specific binding to DAT and VMAT2 is reduced in MA treated mice.
A small decrease in DAT mRNA levels in substantia nigra was shown in MA
lesioned female mice by in situ hybridization but this decrease was
prevented by administration of Estradiol benzoate.6
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17. Neuroprotection by Androgens:
 Testosterone potential for neuroprotective effect was also assessed with MA toxin. Acute
or chronic administration of testosterone did not protect against MA induced striatal DA
depletion in experimental animals.6
• In MPTP treated mice, DA depletion,
DAT and VMAT2 specific binding and
DAT mRNA levels was not prevented by a
pre and post treatment with testosterone or
dihydrotestosterone rather effect of MPTP
was increased by testosterone on DAT
mRNA levels.
• This suggests that dose of testosterone
used is not transformed into 17-ᵦ estradiol
in the brain in sufficient concentrations so
as to reach the protective levels.
Fig.5
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18. Neuroprotection by Progesterone:
 A low dose of progesterone prevents MPTP induced striatal DA depletion in intact
male mice.
 Pre-treatment with high dose of progesterone reduced DA levels in MA treated
ovariectomized female mice whereas MA toxicity was decreased in gonadectomized
male mice at low doses.
 2 days pre-treatment of estradiol benzoate followed
by 1 day treatment with progesterone resulted in
increased DA content in MA treated female mice.
 Hence, much is to be done on the structure activity
relationship of progestin neuroprotection of
dopaminergic system.6
Cholesterol
TSPO
Pregnenolone
3ᵦ HSD
Progesterone
•Neuroregenration
•Myelination
•Neuroprotection
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19. Neuroprotection by Estrogen Receptors:
 In mice striatum, 2 types of estrogen receptors i.e. ERα and ERᵦ have been detected.
 Male mice when treated with ERα
agonist showed protection against
MPTP induced decrease in DA and
DAT specific binding
 But when the same animal was
treated with ERᵦ agonist and
androstenediol, did not show any
protection.
 Thus it suggested that ERα was
involved in neuroprotection.
 Another experiment suggested that
for neuroprotection both the
estrogen receptors are necessary.7
E2
•Puberty
•Sexual characteristics
•Reproduction
D1and D2
receptor
activation
Increased GABA A
signaling
•Learning
•Memory
•Aggression
•Mood
•Cognition
•Reduced
inflammation
•Increased
neuroprotection
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20. MAPK and PI3K/Akt Signaling Pathways in Neuroprotection
against MPTP and MA toxicity:
ER is responsible for activating MAPK/PI3K.
Activated MAPK/ ERK 1/2 then translocates to the nucleus where transcription factors
such as cAMP-response element binding protein (CREB) and ERE are activated.
Involved in neuroprotection
 In MPTP mice, treatment with 17 ᵦ estradiol/ PPT increased phosphorylation of
Akt.
 Phosphorylated GSK3ᵦ was decreased in MPTP mice but this effect was prevented
by PPT.
 These results suggest that activation of Akt pathway is involved in the
neuroprotective effect.
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21.  Phosphorylation of CREB (cAMP-response element binding protein ), inhibition of
GSK3 (active kinase ) activity and up regulation of Bcl-2 expression is all actions of
estrogens.
 17-ᵦ estradiol protects against glutamate and ᵦ amyloid induced toxicity in cultured
neurons through a mechanism suggesting the PI3K/ Akt signaling pathway. 3
Endogenous Estrogens Exposure in PD:
 Age of women at menopause, menarche and hysterectomy are the factors that have
an impact on exposure of a woman to endogenous ovarian hormones during her life
expectancy.
 A more than few studies explored the theory that a PD risk can be reduced if there is
longer exposure to endogenous estrogens.
 Women with Parkinson’s disease encountered an early menopause with a shorter
reproductive life expectancy.
 Elements diminishing estrogen stimulation during life is related with PD.8
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22. Hormone therapy in PD:
 Decreased risk of PD was
related with utilization of
postmenopausal hormone therapy.
 It was investigated that current users of estrogen along with progestin formulation
for less than five years had a higher risk of PD than users using the combination for
more than five years.
 The utilization of estrogen therapy in hysterectomized women is related with an
expanded risk of disease in relation to the women who experienced natural
menopause.
 In a study of hormone therapy formulation it has been evaluated that there is an
increased risk of PD which has been observed with the utilization of esterified
estrogens when used in combination with progestin. However, same effect was not
present with the utilization of conjugated equine estrogens (with/without progestin).
 Starting hormonal therapy during late post menopause increases the chances of
dementia and it does not prevent mild cognitive impairment while initiating therapy
during peri-menopause had beneficial effect on the brain.8
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23. Contraceptive Pills in PD management:
 Inconsistent results have been reported.
 Few studies say that use of oral
contraceptive pills for five years or more is
associated with increased risk of PD where
as some reported this with the use pills for
more than six months.
 In contrast to this, a study described that
use of contraceptives for more than 10 years was associated with a decreased risk of
PD.
 In some studies no association was found between use of oral contraceptives and PD
risk.
 There are two types of contraceptives available:
a. Combined Pills (Estrogens And Progestins)
b. Progestins only pills.
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24.  The first hormonal pill was introduced in 1957 Enovid.
 The first combined pill contained Mestranol, which is demethylated to ethinyl
estradiol, and norethynodrel.
 Mestranol is a progestin derived from testosterone, which has some
androgenic activities.
 This pill contained high dose of ethinyl estradiol i.e. 150 µg and norethynodrel
i.e. 9.85 mg.
 3 types of progestins:
a. Testosterone b. Progesterone c. Spironolactone derivative
 All progestins bind with relatively different affinity to the progesterone
receptor and they may also bind to other steroid receptors which are androgen,
glucocorticoid and mineralocorticoid receptors.
 Newer progestins discovered are more specific to the progesterone receptor
and has less affinity for other steroid receptors thus it decreases androgenic,
estrogenic and glucocorticoid adverse effects.9
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25. CC BY- SA- NC25
Acknowledgement
I would like to express my special thanks of gratitude to my guide Mr. Vivek
Srivastava, Assistant prof. Amity Institute of Pharmacy, Amity University,
Lucknow campus who gave me golden opportunity to do this project on the
topic Gonadocorticoids: A Potential Treatment for Parkinson’s disease.
I would also like to underscore the dynamic efforts of Massive Open Online
Course; Academic Writing course (UGC) for their expert advise and
contributions to the preparation of this presentation.
Last but not the least I want to thank my parents and friends who were also a
backbone to this work.

26. REFERENCES:
1. Melanie Bourque, Marc Morissette, et al. Repurposing Sex Steroids and
Related Drugs as a Potential Treatment for Parkinson’s Disease.
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2. Saleh Mohamed. Female Sex Hormones. Research Gate. 2016 Jan.
3. Melanie Bourque, Dean E Dluzen, Therese Di Paolo. Neuroprotecive
Actions of Sex Steroids in Parkinson’s disease. Frontiers in
Neuroendocrinology 30 (2009): 142- 157.
4. Adams C. Kumar. The Effect of Estrogen in a Man with Parkinson's
disease and a Review of Its Therapeutic Potential. Int J Neurosci. 2013;
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5. Susanne Arnold, Marion Barbena Victor, Cordian Beyer. Estrogen and the
Regulation of Mitochondrial Structure and Function in the Brain. Journal
of Steroid Biochemistry and Molecular Biology 131 (2012): 2-9.
6. Bourque M, Morissette M, Al Sweidi S, et al. Neuroprotective Effect of
Progesterone in MPTP-Treated Male Mice. Neuroendocrinology.2016;
103: 300-314.
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27. 7. Baraka, Korish, Solima, Kamal. The Possible Role of Estrogen and
Selective Estrogen Receptor Modulators in a Rat Model of Parkinson's
disease. Life Sci. 2011; 88: 879-885.
8. Bhavnani B. R, Stanczyk F. Z. Pharmacology of Conjugated Equine
Estrogens: Efficacy, Safety and Mechanism of Action. J Steroid Biochem
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9. Burke A. E. The State of Hormonal Contraception Today: Benefits And
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28. THANK YOU
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