Plantas medicinales y terapias alternativas en
     Alzheimer. Una tierra desconocida


 Laboratorio de Fisiología de la Reproducción

                 Jorge Parodi
               jparodi@uct.cl
http://www.alz.org/alzheimers_disease_alternative_treatm
ents.asp

                  Caprylic acid and coconut oil
                  Concerns
                  Coenzyme Q10
                  Coral calcium
                  Ginkgo biloba
                  Huperzine A
                  Omega-3 fatty acids
                  Phosphatidylserine
                  Tramiprosate
Test                     Placebo                  Ginko
       Memory                           0,15                     0,14
       Executive test                   3,27                     3,47

 Conclusion Compared with placebo, the use of G biloba, 120 mg twice daily, did
 not result in less cognitive decline in older adults with normal cognition or with mild
 cognitive impairment.




Snitz et al 2009 JAMA
From: Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: A Randomized
Trial
JAMA. 2010;304(17):1903-1911. doi:10.1001/jama.2010.1510




                                           Copyright © 2012 American Medical
Date of download: 7/14/2012
                                             Association. All rights reserved.
Donepezil and Memantine for Moderate-to-
                               Severe Alzheimer's Disease

                               Conclusions

                               In patients with moderate or severe Alzheimer's
                               disease, continued treatment with donepezil was
                               associated with cognitive benefits that exceeded the
                               minimum clinically important difference and with
                               significant functional benefits over the course of 12
                               months
                                                                         JAMA 2012




Danitz and Parsons 2008 IJNP
Palmer 2002 Trends in Phar
Benilova et al 2012 Nature Neuroscience
Agregados A                 1-40   se localizan en regiones sinápticas
                MAP1B – Cy3         A                               D
A – DAC (1:2)
24 horas                                             H
0.5 M




                A - DAC             B



                                                                G




                SV2 – Cy5           C                      G



                                                           H

                                                         10 m
Parodi et al (2010) JBC
Savonenko et al (2005) Neurobiology of Disease
Dinamarca et al (2006) Molecular Psychiatry
Inestrosa et al (2011) Translation Psychiatry
Montesinos et al (2012) in report
1,2
                                                                  Control
                                                                  5 mM Etanol
                                                    1,0           10 mM Etanol
                        A       B                                 50 mM Etanol




                                    (D.O. 405 nm)
                                     Turbimetria
                                                    0,8

                                                    0,6

                                                    0,4

                                                    0,2

                                                    0,0

                                                              0          50      100    150   200
                                                                              Tiempo (min)

                        C                                 D                      Modeling           E




Ormeño et al (2012) in review
A   B




C   D
A                                         B



                        LYS-28                                  LYS-28

                                                                 2.7Ẳ


       ASP-23
                                                       ASP-23



C                                LYS-28   D

                12.7Ẳ
                                                                LYS-28

                                                       6.3Ẳ
                                              ASP-23
    ASP-23
A                                                     B
    12                                                                   25
               Control                                                              Control
               Ethanol 10 %                                                         Ethanol 1%
    10                                                                   20




                                                      Deviation (RMSD)
    8                                                                    15
Ẳ




    6
                                                                         10

    4
                                                                         5

    2
                                                                         0
    0
         0,0        0,5       1,0   1,5   2,0   2,5                           0,0      0,5        1,0   1,5   2,0   2,5

                          Time (ns)                                                              Time (ns)
2,5




                                                             Actividad Sináptica Espontánea
                                                                                                                     Agregados amilodes
                                                                                              2,0




                                                                     Frecuencia (Hz)
                                                                                              1,5

                                                                                                                            *
                                                                                              1,0
                                                                                                                      *
  Control
                                                                                                             *
                                                                                              0,5




                                                    20 pA
                                                                                                                 *
                                            0.2 s
                                                                                              0,0
  Agregados A 0.5 M (24 h)




                                                                                                                          10

                                                                                                                                25

                                                                                                                                     50


                                                                                                                                            0
                                                                                                                 1

                                                                                                                     5
                                                                                                           as
                                                                                                            ol




                                                                                                                                          10
                                                                                                          tr

                                                                                                         ad
                                                                                                        on
                                                    20 pA




                                                                                                       at
                                                                                                                          Etanol (mM)




                                                                                                     C

                                                                                                    Tr
                                            0.2 s
  Agregados A 0.5 M + 10 mM Etanol (24 h)




                                                    20 pA
                                            0.2 s
  Agregados A 0.5 M + 50 mM Etanol (24 h)
                                                            Sv2


                                                    20 pA
                                            0.2 s
  50 mM Etanol (24 h)
                                                    20 pA




                                            0.2 s



                                                                                                                                           A aggregates 0.5 M




Ormeño et al (2012) in review
A                                                                       B                                                                                             C
                                                                                                                                                                                                   8
                   1,5                                                                               -1000                                                                   Aggregate




                                                                        Membrane conductances (nS)
                              Control
                              Gramicidin                                                                                                                                     Gramicidin            6
Number of events




                              Amphotericin B                                                                                                                                 Amphotericin
                              Aggregate                                                               -800
                                                                                                                                 *                                           Control               4
                   1,0                                                                                                                                            *
                                                                                                      -600                                           *                                             2
                                                                                                                                                                        mV
                                                                                                                                                                                                   0
                                                                                                      -400                                                            -200   -150     -100   -50        0        50   100
                   0,5
                                                                                                                                                                                                   -2
                                                                                                      -200
                                                                                                                                                                                                   -4

                   0,0                                                                                  0                                                                                          -6
                         -6   -5     -4        -3    -2    -1   0   1




                                                                                                                                                                  s
                                                                                                                 ol




                                                                                                                            in




                                                                                                                                                 B




                                                                                                                                                                te
                                                                                                                                                                                                            nA
                                                                                                               tr




                                                                                                                            id




                                                                                                                                                in
                                               Amplitude (nA)




                                                                                                                                                              ga
                                                                                                             on




                                                                                                                          ic




                                                                                                                                              ic
                                                                                                                                                                                                   -8




                                                                                                                                                            re
                                                                                                                        m




                                                                                                                                           er
                                                                                                             C




                                                                                                                      ra




                                                                                                                                                          gg
                                                                                                                                        ot
                                                                                                                      G




                                                                                                                                      ph




                                                                                                                                                         A
                                                                                                                                      m
                                                                                                                                     A




Parodi et al (2012) in review
A                                                                                  B
              Control
                                                                                                                    300




                                                                                          (% of control at 20 mV)
                  High   Ca2+
                                                                                                                                                                    *




                                                                      Current amplitude
                  NR                                                                                                250
                                                          + 20 mV
                                                             0 mV




                                                                                          +
                                                                                                                    200
                                                          -100 mV                                                                      *
                                                                                                                    150                             *
              Aggregate
                                                 100 nA
                                                          250 ms                                                    100
                  High   Ca2+
                  NR                                                                                                 50
                                                           + 20 mV
                                                              0 mV                                                    0
                                                           -100 mV                                                        NR      High Ca2+         NR       High Ca2+
                                                                                                                                                        Aggregate

                                                                                                                    200
 C                                                                                  D




                                                                     Current amplitude
                                                                                                                                                              *




                                                                       (% of control )
                                NR            15 min Aggregate                                                      150           NR
                       0 min         15 min
Rabbit serum
                                                                                                                    100



                                                                                                                    50
     200 nA




                                                                                                                     0
              4 min
                                                                                                                          0 min            15 min   15 min Aggregate
NR                                              15 min Aggregate

             0 min                    15 min
100 μM ATP



                                                                        120
                                               Current (% of control)




                                                                        100


                                                                        80


                                                                        60


                                                                        40
                                                                                                           *
                     200 nA




                                                                        20


                                                                         0
                               60 s                                              0 min      15 min   15 min Aggregate
Agradecimientos
Dr. Luis Aguayo
Dr. Nibaldo Inestrosa
Fernando Sepulveda
David Ormeño

Laboratorio de Fisiología de la Reproducción
Felipe
Guillermo
Daniela

Colaboradores
Dr. Alexander Ortloff
MsC Patricio Peña

Presentación nucleo uct 2012 ii

  • 1.
    Plantas medicinales yterapias alternativas en Alzheimer. Una tierra desconocida Laboratorio de Fisiología de la Reproducción Jorge Parodi jparodi@uct.cl
  • 5.
    http://www.alz.org/alzheimers_disease_alternative_treatm ents.asp Caprylic acid and coconut oil Concerns Coenzyme Q10 Coral calcium Ginkgo biloba Huperzine A Omega-3 fatty acids Phosphatidylserine Tramiprosate
  • 6.
    Test Placebo Ginko Memory 0,15 0,14 Executive test 3,27 3,47 Conclusion Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment. Snitz et al 2009 JAMA
  • 7.
    From: Docosahexaenoic AcidSupplementation and Cognitive Decline in Alzheimer Disease: A Randomized Trial JAMA. 2010;304(17):1903-1911. doi:10.1001/jama.2010.1510 Copyright © 2012 American Medical Date of download: 7/14/2012 Association. All rights reserved.
  • 8.
    Donepezil and Memantinefor Moderate-to- Severe Alzheimer's Disease Conclusions In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months JAMA 2012 Danitz and Parsons 2008 IJNP
  • 9.
  • 10.
    Benilova et al2012 Nature Neuroscience
  • 12.
    Agregados A 1-40 se localizan en regiones sinápticas MAP1B – Cy3 A D A – DAC (1:2) 24 horas H 0.5 M A - DAC B G SV2 – Cy5 C G H 10 m
  • 13.
    Parodi et al(2010) JBC
  • 16.
    Savonenko et al(2005) Neurobiology of Disease
  • 17.
    Dinamarca et al(2006) Molecular Psychiatry
  • 18.
    Inestrosa et al(2011) Translation Psychiatry
  • 19.
    Montesinos et al(2012) in report
  • 20.
    1,2 Control 5 mM Etanol 1,0 10 mM Etanol A B 50 mM Etanol (D.O. 405 nm) Turbimetria 0,8 0,6 0,4 0,2 0,0 0 50 100 150 200 Tiempo (min) C D Modeling E Ormeño et al (2012) in review
  • 22.
    A B C D
  • 23.
    A B LYS-28 LYS-28 2.7Ẳ ASP-23 ASP-23 C LYS-28 D 12.7Ẳ LYS-28 6.3Ẳ ASP-23 ASP-23
  • 24.
    A B 12 25 Control Control Ethanol 10 % Ethanol 1% 10 20 Deviation (RMSD) 8 15 Ẳ 6 10 4 5 2 0 0 0,0 0,5 1,0 1,5 2,0 2,5 0,0 0,5 1,0 1,5 2,0 2,5 Time (ns) Time (ns)
  • 25.
    2,5 Actividad Sináptica Espontánea Agregados amilodes 2,0 Frecuencia (Hz) 1,5 * 1,0 * Control * 0,5 20 pA * 0.2 s 0,0 Agregados A 0.5 M (24 h) 10 25 50 0 1 5 as ol 10 tr ad on 20 pA at Etanol (mM) C Tr 0.2 s Agregados A 0.5 M + 10 mM Etanol (24 h) 20 pA 0.2 s Agregados A 0.5 M + 50 mM Etanol (24 h) Sv2 20 pA 0.2 s 50 mM Etanol (24 h) 20 pA 0.2 s A aggregates 0.5 M Ormeño et al (2012) in review
  • 27.
    A B C 8 1,5 -1000 Aggregate Membrane conductances (nS) Control Gramicidin Gramicidin 6 Number of events Amphotericin B Amphotericin Aggregate -800 * Control 4 1,0 * -600 * 2 mV 0 -400 -200 -150 -100 -50 0 50 100 0,5 -2 -200 -4 0,0 0 -6 -6 -5 -4 -3 -2 -1 0 1 s ol in B te nA tr id in Amplitude (nA) ga on ic ic -8 re m er C ra gg ot G ph A m A Parodi et al (2012) in review
  • 28.
    A B Control 300 (% of control at 20 mV) High Ca2+ * Current amplitude NR 250 + 20 mV 0 mV + 200 -100 mV * 150 * Aggregate 100 nA 250 ms 100 High Ca2+ NR 50 + 20 mV 0 mV 0 -100 mV NR High Ca2+ NR High Ca2+ Aggregate 200 C D Current amplitude * (% of control ) NR 15 min Aggregate 150 NR 0 min 15 min Rabbit serum 100 50 200 nA 0 4 min 0 min 15 min 15 min Aggregate
  • 29.
    NR 15 min Aggregate 0 min 15 min 100 μM ATP 120 Current (% of control) 100 80 60 40 * 200 nA 20 0 60 s 0 min 15 min 15 min Aggregate
  • 31.
    Agradecimientos Dr. Luis Aguayo Dr.Nibaldo Inestrosa Fernando Sepulveda David Ormeño Laboratorio de Fisiología de la Reproducción Felipe Guillermo Daniela Colaboradores Dr. Alexander Ortloff MsC Patricio Peña