ITD PRESENTATION PART-3

CHANGES:

In India there are 4 million people suffering from AD and the estimated liability is almost 7.5 million by
the end of 2030.

PATHOPHYSIOLOGY OF CURCUMIN:

How curcumin inhibit amyloid beta - curcumin 208 has been demonstrated to inhibit aggregation and
promote disaggregation of fibrillar Aβ in vivo and in in vitro.

This mechanism may be due to the structure of curcumin: an in-vitro study postulated that the
hydrophobicity of curcumin or the interaction between the keto or enol rings of curcumin and aromatic
rings of Aβ dimers destabilised the attraction requisite for the formation of beta-sheets in Aβ plaques.

In addition, curcumin’s polar hydroxy groups on the two aromatic rings of the molecule interact with
polar pockets of the Aβ peptide, rendering it suitable to destabilize beta-sheets.

The inflexible linker between the two aromatic rings is conductive to this binding property.

How curcumin inhibit tau: GSK-3β is an enzyme that adds phosphate groups onto serine and threonine
amino acid residues and regulates the phosphorylation of tau. Accordingly, inhibition of GSK-3β may
protect cells from tau-induced neurotoxicity and curcumin has been identified as such an inhibitor.

CURRENT THERAPY AND LIMITATION:

DRUG COMPANY BRAND APPROVED INHIBITS APPROVED MARKET REF
NAME FOR DATE PRODUCT
Tacrine The Cognex Mild to Ache In 10 Sept
WarnerLambert moderate 1993
company
Donepezil Eisai. America Aricept All stages Ache In 21 May
1996

Rivastigmine Novartis Exelon All stages Ache In 21 April

Pharmaceuticals 2000
Corporation
Galantamine Janssen Razadyne Mild to Ache In 28 Feb
Research severe 2001
Foundation
Memantine Forest Namenda Moderate NMDA 16 Oct
Laboratories to severe Ant 2003

Donepezil+ Forest Namzaric Moderate Ache In 23 Dec

Mematine Laboratories to severe + 2014
NMDA
Ant
ADVERSE DRUG REACTION OF CURRENT THERAPY.

1. Aricept: The most common adverse events, defined as those occurring at a frequency of at least
5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by
ARICEPT’s cholinomimetic effects. These include nausea, diarrhoea, insomnia, vomiting, muscle
cramp, fatigue and anorexia.
2. Rivastigmine: A wide range of adverse events which were consistent with the anticholinergic
properties of rivastigmine were reported, including gastrointestinal adverse events such as
nausea, vomiting, abdominal pain or discomfort, and diarrhoea. Other adverse events reported
included falls, insomnia, agitation, weight loss, headache, dizziness, and cutaneous adverse
events where patches were used.

Known and less know adverse reaction of alzheimer’s drugs

Known adverse reaction

Nausea diarrhea

Vomittiing anorexia
Less known adverse reaction

Rhinitis headaches
Fatique bradycardia
Insomnia orthostatic hypotension
Leg cramps syncope
Abdominal dreams urinary incontinence
Myasthenia seizures
Asthenia gastrointestinal bleeding
Tremor hepatitis
Dizziness extrapyramidal symptoms
Reference

Cummings JL. Use of cholinesterase inhibitors in clinical practice: Evidence-based

recommendations. Focus 2004;2(2):239-252.

Inglis F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. Int J
Clin Pract Suppl 2002;(127):45-63.

Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer ’s disease:

Epidemiology and management. Drugs Aging 2001;18(11):853-862.

https://www.consultant360.com/articles/adverse-effects-acetylcholinesterase-inhibitors

NOAEL OF CURRENT THERAPY:

CHART BY RAINI

CURCUMIN:
Curcumin approved by the USFDA as “Generally Recognized As Safe” (GRAS) where, it possess good
tolerability and safety in human trials, doses between 4000 and 8000 mg/day - SONAL

Curcumin has a widespread role in many disease illnesses such as anti-inflammatory, anti-cancer
properties, lead stop inhibition of cell signalling pathways at multiple levels, it has ability to affect the
apoptosis and gene transcription in preclinical models. The result of curcumin was premeditated in
patients with rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic
pancreatitis, psoriasis, hyperlipidaemia, and cancers.

CURCUMIN PROFILE
Family zingiberaceae
Species Curcuma longa
Chemical constituents curcumin is a diarylheptanoid, belonging to the
group of curcuminoids, which
are phenolic pigments responsible for the yellow
colour of turmeric.
Chemical name (1E,6E)-1,7-bis (4-hydroxy- 3-methoxyphenyl) -
1,6- heptadiene-3,5-dione
IUPAC name (1E,6E)-1,7-bis (4-hydroxy- 3-methoxyphenyl) -
1,6- heptadiene-3,5-dione
Molecular formula C21H20O6
Molecular weight 368.38g/mole
Structure

Keto form

Enol form

Mechanism of action of curcumin in alzheimer disease: as it is in slides

Adme:

POOR ABSORPTION
The majority of oral curcuminis
excreted in the feces (≤90%).
poor solubility and stability in GIT.

RAPID SYSTEMIC ELEMINATION CHEMICAL INSTABILITY

Generally, the oral
bioavailability of curcumin is
low due to a relatively low
absorption by small
intestine coupled to an
extensive reductive and
conjugative metabolism in
the liver and an elimination
through the gall bladder.
At, physiological pH,
curcumin rapidly degrades
to bicyclopentadione
Drawbacks through autoxidation,
of
with cleavage products
such as bicyclopentadione,
CURCUMIN vanillin, and ferulic acid
being formed.

RAPID METABOLISM
curcumin undergoes rapid
metabolic reduction and
conjugation, resulting in poor
systemic bioavailability after oral
administration.
 How the drawback was overcome: Liposomes, nanoparticles, micelles, phytosomes, and
adjuvants play a role in increasing bioavailability of drugs by reducing their drawbacks.

Targets in metabolism step:

Curcumin

UDP
β glucuronidase generate
inhibit glucuronosyltransfer
enzyme
ase enzyme

Curcumin metabolite

Rapid elimination
VITAMIN A as an UGT inhibitor:

Vitamin A is an inhibitor of UDP-Glucuronosyltransferase Enzymes. It blocks enteric and hepatic

glucuronidation, which leads to higher curcumin in plasma and tissue levels. Hence, by combination we
can slow the breakdown of curcumin, leaving more available for the body to use as well as produce
synergistic effect.

Vitamin A inhibits the UGTs mentioned as UGT1A1, UGT1A3, UGT1A9, UGT2B7.

Vitamin A role in Alzheimer’s disease:

• Vitamin A, which is synthesized by the central nervous system (CNS) more than by any other
organ, regulates a number of genes that are expressed in the CNS.

• In addition, it plays important roles in the development of the CNS.

• Vitamin A, which has been traditionally considered to be an anti-oxidant compound, plays a role
in maintaining higher CNS functions in older subjects. AD patients have been reported to have
low serum and plasma concentrations of vitamin A and b-carotene.

• It has been reported that, among 442 patients (aged 65–94 years), a higher plasma
concentration of b-carotene was associated with better memory performance.

• Oligomerization of Aβ fibrils is an important mechanism contributing to neuronal toxicity in AD.

Vitamin A has shown to decrease the aggregation and oligomerization of Aβ40 and Aβ42 fibrils.

• Previously, reported that vitamin A and b-carotene dose-dependently inhibited the formation of
b-amyloid fibrils (fAb) from fresh Ab, and also dose-dependently destabilized preformed fAb in
vitro. Recently, showed the inhibitory effects of vitamin A and b-carotene on the oligomerization
of Ab40 and Ab42 in vitro. In the present review, summarized recent studies of Ab aggregation,
and the effect of vitamin A and b-carotene on this aggregation, and have discussed the potentials
of these compounds as candidates for preventive and therapeutic agents for AD.

COMBINE MECHANISM OF CURCUMIN-VITAMIN A FORTIFIED YOGURT:

 Estimated Lifetime Risk for Alzheimer’s Dementia, by
Sex, at Ages 45 and 65
25

20
PERCENTAGE

15

10

0
45 65

AGE

MEN WOMEN
 CURCUMIN

METABOLISED BY REGENERATE BY

UDP-
GLUCURONOSYLTRANSFERSE β-GLUCURONIDASE ENZYME
ENZYME

INHIBITED BY INDUCED BY

VITAMIN A L.RHAMNOSUS

CURCUMIN BIOAVAILABILITY
INCREASES

ALZHEIMER’S
DISEASE
SR.NO UGT-ENZYME INHIBITORS REFERENCE
1 UGT1A9 Phenytoin Kostubsky Et. Al.
2005
2 UGT1A9 Mefenamic Acid Vietri Et Al. 2000
3 UGT2B7 Fluconazole Uchaipichat Et Al.
2006
4 UGT2B7 Vitamin A Liu Et Al. 2017
5 UGT2B7 Flunitrazepam Ghosal Et Al.
2004
GROUP 1 GROUP 2 GROUP 3

CONTROL STZ INDUCED(2mg/kg) VITAMIN A

GROUP 4

CURCUMIN

GROUP 7 GROUP 6 GROUP 5

STANDARD CURCUMIN-VIT A- YOGURT

FORTIFIED YOGURT
 ALZHEIMER’S
DISEASE

INHIBITION of INHIBIT Aβ PLAQUES AND TAU INCREASE expression

oligomerization of of GABA – improve
aβ-40 and aβ-42 cognition deficits

CURCUMIN

UDP- β-
VITAMIN A GLUCURONIDASE L.RHAMNOSUS
GLUCURONOSYLTR
ANSFERASE ENZYME
ENZYME

CURCUMIN
GLUCURONIDASE

RAPID
EXCRETION

FACES AND
URINE
SR. TREATMENT [KG/DAY] NO.
NO GROUP CONTROL CURCUMIN VITAMIN A YOGURT CURCUMIN- STANDARD - ANIM
Saline[ml] [mg/kg] [IU] [CFU] VITAMIN A- DONEPENZIL
FORTIFIED [mg/kg]
YOGURT
[CFU]
ROUTE OF ORAL ORAL ORAL ORAL ORAL ORAL
ADMINISTRATIO
N
1 GROUP 1 Saline - - - - - 08
2 GROUP 2 - 2g/kg/day - - - - 08
3 GROUP 3 - - 3000 - - - 08
mcg/kg/day
4 GROUP 4 - - - 107 CFU - - 08
5 GROUP 5 - - - - Cur-2g/kg/day - 08
Vit
A-3000mcg/kg/d
ay
Yogurt-107 CFU
6 GROUP 6 - - - - - 10mg/kg 08
TOTAL NO. OF ANIMALS 48
DURATION OF TREATMENT AFTER SURGERY ON
ON
 MALE WISTAR RAT (n=56)
N=no. of animals

GROUP 1 [n=8]
GROUP 2 [n=8] GROUP 3 [n=8] GROUP 4 [n=8] GROUP 5 [n=8] GROUP 6 [n=8]

CONTROL CURCUMIN VIATMIN A STANDARD-

CURCUMIN-
(oral) (oral) (oral) YOGURT (oral) Donepenzil
VITAMIN A-
(oral)
400mg/kg ˣ 10 FORTIFIED
Saline 10,000 IU ˣ 10 107 ˣ 10 days
days YOGURT (oral) 10mg/kg ˣ 10
[ml]ˣ10days days
days
Application no. Source Title

CN 202010087077 https://www.lens.org Composition capable of improving

water solubility of curcumin and
application of composition in
preparation of compound for
treating Alzheimer’s Disease

https:// Formulation of curcumin with

EP11765166A worldwide.espacenet.com enhanced bioavailability
of curcumin and method of
preparation and treatment thereof
US201916969759A https:// Probiotic formulations for the
worldwide.espacenet.com treatment and alleviation of
metabolic and oxidative stress,
inflammation and
neurodegeneration
CN201711204454A https://
Vitamin composition for improving
worldwide.espacenet.com
cognitive function
of Alzheimer's disease and purpose

INA201911037189 https://ipindiaservices.gov.in Curcumin – protein health

supplement for overall health with
increased bioavailability by piperine
(1)1. Ahmadi S, Zobeiri M, Bradburn S. Molecular mechanisms underlying actions of
certain long noncoding RNAs in Alzheimer’s disease. Metab Brain Dis.
2020;35(5):681–93.

2. Alzheimer’s Association. 2021 Alzheimer’s disease facts and figures special report
Race, Ethnicity and Alzheimer’s in America. Alzheimers Dement. 2021;17(3):327–
406.

3. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT.
Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s Dement
Transl Res Clin Interv. 2018;4:575–90.

4. Kumar Thakur A, Kamboj P, Goswami K, Ahuja K. Pathophysiology and

management of alzheimer’s disease: an overview. J Anal Pharm Res. 2018;7(2):226–
35.

5. Morsy A, Trippier PC. Current and Emerging Pharmacological Targets for the
Treatment of Alzheimer’s Disease. J Alzheimer’s Dis. 2019;72(s1):S145–76.

6. Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, et al. Current
state of Alzheimer’s fluid biomarkers [Internet]. Vol. 136, Acta Neuropathologica.
Springer Berlin Heidelberg; 2018. 821–853 p. Available from:
https://doi.org/10.1007/s00401-018-1932-x

7. current therapy.

8. Each I, Agent AI, Code IATC, Saint-laurent TH, Revision P, No SC. aricept Product
monograph. 2014;(180582):1–38.

9. Js B, J GE, Birks JS, Evans JG. Rivastigmine for Alzheimer ’ s disease ( Review )
Rivastigmine for Alzheimer ’ s disease. Cochrane Database Syst Rev. 2015;(4):4–7.

10. exelon epar scientific. 2005;(April 2003):1–15.

11. FDA approved drug Products. Razadyne, Prescribing information. Prescr Inf. 2001;

12. namzaric. 2014;

13. Basnet P, Skalko-Basnet N. Curcumin: An anti-inflammatory molecule from a curry

spice on the path to cancer treatment. Molecules. 2011;16(6):4567–98.

14. Mishra S, Palanivelu K. The effect of curcumin ( turmeric ) on Alzheimer ’ s disease :

An overview Introduction Curcumin and Alzheimer ’ s Disease Epidemiological
Studies Curcumin as an Anti Inflammatory in Alzheimer ’ s Curcumin as an Anti-
oxidant. Ann Indian Acad Neurol. 2008;11(1):13–9.

15. Lopresti AL. The problem of curcumin and its bioavailability: Could its
gastrointestinal influence contribute to its overall health-enhancing effects? Adv
Nutr. 2018;9(1):41–50.

16. Kharat M, Du Z, Zhang G, McClements DJ. Physical and Chemical Stability of

 Curcumin in Aqueous Solutions and Emulsions: Impact of pH, Temperature, and
Molecular Environment. J Agric Food Chem. 2017;65(8):1525–32.

17. Verghese. pharmacokinetics of curcumin conjugate metabolites in healthy human

subjects. Bone. 2011;23(1):1–7.

18. Cas MD, Ghidoni R. Dietary curcumin: Correlation between bioavailability and
health potential. Nutrients. 2019;11(9):1–14.

19. Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: Their role
in drug metabolism and detoxification. Int J Biochem Cell Biol [Internet].
2013;45(6):1121–32. Available from: http://dx.doi.org/10.1016/j.biocel.2013.02.019

20. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, et al. Phenobarbital
and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-
glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci.
2005;87(1):146–55.

21. Vietri M, Pietrabissa A, Mosca F, Pacifici GM. Mycophenolic acid glucuronidation and
its inhibition by non-steroidal anti-inflammatory drugs in human liver and kidney.
Eur J Clin Pharmacol. 2000;56(9–10):659–64.

22. Uchaipichat V, Winner LK, MacKenzie PI, Elliot DJ, Williams JA, Miners JO.
Quantitative prediction of in vivo inhibitory interactions involving glucuronidated
drugs from in vitro data: The effect of fluconazole on zidovudine glucuronidation. Br
J Clin Pharmacol. 2006;61(4):427–39.

23. Liu X, Cao YF, Dong PP, Zhu LL, Zhao Z, Wu X, et al. The inhibition of UDP-
glucuronosyltransferases (UGTs) by vitamin A. Xenobiotica. 2017;47(5):376–81.

24. Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, et

al. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for
the glucuronidation of ezetimibe (ZETIA). Drug Metab Dispos. 2004;32(3):314–20.

25. Ono K, Yamada M. Vitamin A and Alzheimer’s disease. Geriatr Gerontol Int.
2012;12(2):180–8.

26. Ozawa H, Imaizumi A, Sumi Y, Hashimoto T, Kanai M, Makino Y, et al. Curcumin β-D-
glucuronide plays an important role to keep high levels of free-form curcumin in the
blood. Biol Pharm Bull. 2017;40(9):1515–24.

27. Patel C, Pande S, Acharya S. Potentiation of anti-Alzheimer activity of curcumin by

probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory
impairment in mice. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(10):1955–
62.

28. Bostanciklioğlu M. The role of gut microbiota in pathogenesis of Alzheimer’s

disease. J Appl Microbiol. 2019;127(4):954–67.

29. Moreira-Silva D, Vizin R, Martins T, Ferreira T, Almeida M, Carrettiero D. Intracerebral

 Injection of Streptozotocin to Model Alzheimer Disease in Rats. Bio-Protocol.
2019;9(20):1–12.

30. Kuszewski JC, Wong RHX, Howe PRC. Can curcumin counteract cognitive decline?
Clinical trial evidence and rationale for combining ω-3 fatty acids with curcumin.
Adv Nutr. 2018;9(2):105–13.

31. 葛川繁. Vitamin A 大量投与による内耳奇形の胎生学的研究. J Osaka City Med

Cent. 1960;9(5).

32. Kneifel W, Jaros D, Erhard F. Microflora and acidification properties of yogurt and
yogurt-related products fermented with commercially available starter cultures. Int
J Food Microbiol. 1993;18(3):179–89.

33. Maurya N, Khamrui K, Prasad W. Studies on curcumin fortification in different lassi

types using Tween-80 as a binding material. Indian J Dairy Sci. 2020;73(6):628–31.

34. Ilic DB, Ashoor SH. Stability of Vitamins A and C in Fortified Yogurt. J Dairy Sci.
1988;71(6):1492–8.

35. Shin CY, Kim HS, Cha KH, Won DH, Lee JY, Jang SW, et al. The effects of donepezil,
an acetylcholinesterase inhibitor, on impaired learning and memory in rodents.
Biomol Ther. 2018;26(3):274–81.

36. Manuscript A. NIH Public Access. 2015;88(4):450–67.

37. Barnhart CD, Yang D, Lein PJ. Using the Morris water maze to assess spatial learning
and memory in weanling mice. PLoS One. 2015;10(4):1–16.

38. Kamat PK. Streptozotocin induced Alzheimer’s disease like changes and the
underlying neural degeneration and regeneration mechanism. Neural Regen Res.
2015;10(7):1050–2.

39. Francis PT. The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectr.
2005;10(11 SUPPL. 18):6–9.

40. Lovell MA. update. 2016;89(7):1035–44.

41. Pocernich CB, Butterfield DA. Elevation of glutathione as a therapeutic strategy in

Alzheimer disease. Biochim Biophys Acta - Mol Basis Dis. 2012;1822(5):625–30.

42. Singh A, Kumar A. Comparative Analysis of Intrahippocampal Amyloid Beta (1-42)

and Intracerbroventricular Streptozotocin Models of Alzheimer’s Disease: Possible
Behavioral, Biochemical, Mitochondrial, Cellu lar and Histopathological Evidences.
J Alzheimer’s Dis Park. 2016;06(01):1–7.

43. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, et al. Oral
curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week
randomized, double blind, placebo-controlled study. Alzheimer’s Res Ther
[Internet]. 2012;4(5):43. Available from: http://alzres.com/content/4/5/43
44. Laboratories SMC. Alzheimer ’ s disease ( AD ) model Drug development in AD.
2016;1–12.

45. Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The Essential
Medicinal Chemistry of Curcumin. J Med Chem. 2017;60(5):1620–37.

46. Kraeuter AK, Guest PC, Sarnyai Z. The Y-Maze for Assessment of Spatial Working and
Reference Memory in Mice. Methods Mol Biol. 2019;1916:105–11.

47. Mclagan A, Hales J. Displaced Object Recognition Memory in Rats. Bio-Protocol.

2019;9(8):1–7.

48. Ogren SO, Institutet K, Stiedl O. Encyclopedia of Psychopharmacology. Encycl

Psychopharmacol. 2015;(May).

49. Sanborn V, Azcarate-Peril MA, Updegraff J, Manderino L, Gunstad J. Randomized

clinical trial examining the impact of Lactobacillus rhamnosus GG probiotic
supplementation on cognitive functioning in middle-aged and older adults.
Neuropsychiatr Dis Treat. 2020;16:2765–77.

(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)
(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(28)(44)(46)(47)
(48)(49)

Website:

1. https://www.msdmanuals.com/en-in/professional/neurologic-disorders/delirium-
and-dementia/alzheimer-disease
2. https://www.rxlist.com/namenda-xr-drug.htm
3. https://en.wikipedia.org/wiki/
Curcumin#:~:text=Curcumin+is+a+bright+yellow,food+flavoring
%2C+and+food+coloring.
4. https://www.healthline.com/nutrition/lactobacillus-rhamnosus#what-it-is
5. http://milkfacts.info/Milk%20Processing/Yogurt%20Production.htm
6. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20823_Exelon.cfm
7. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
8. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-169_Reminyl.cfm
9. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-
487_Namenda.cfm
10. https://www.accessdata.fda.gov/drugsatfda_docs/nda/
2014/206439Orig1s000TOC.cfm

11. https://www.noldus.com/blog/y-maze-learning-and-memory-testing
 STZ

GLUT-2 RECEPTOR

Damage β cells Insulin receptor

of pancreas signaling

Insulin deficiency GSK3β

Insulin deficiency
Aβ accumulation Tau phosphorylation
in brain

neuroinflammation Senile plaque Neurofibrillary tangles

Neuronal and synapse

loss

Alzheimer’s Disease
 Intracerebroventricular
Streptozotocin(45)

Neuronal Microglia and NMDA Mitochondrial GSK-α/β

Glucose Astrocytes Receptor Over Dysfunction Activity
Activation

ATP
Selective Vulnerability of
Cholinergic Neurons Free Radical Formation
( AChE activity, ChAT,
Oxidative stress
Ach)
Release of Pro-Inflammatory Mediators

Tau Hyperphosphorylation
Oxidative Stress, DNA
Damage Neuronal Cell Death
Neuroinflammation