9.

:
Parkinson

1. :
2. : , , ,

3. : Parkinson, Alzheimer,
Huntington
4.
5. : , ,

6.
7.

1. :
(Myasthenia gravis)
2.
: Lambert-Eaton, McCardle

1. : , Shy-Drager, Horner
2.

392

. To 1817,
James Parkinson (1755-1824)
6 ,
shaking palsy paralysis agitans. 1877
Jean-Martin Charcot Parkinson.

, (
), , (
),
( ,
James Parkinson
)
(1755-1824)
.
5 20%
. 10-12 80%
.
20 .
Parkinson .
(Schonberg, 1987).
9.1
Parkinson
60 ,
.
Mississippi
( Schonberg, 1987).

Parkinson
Parkinson
1900. 1919, Tretiakoff
(substantia nigra)
Parkinson.
(subtantia nigra pars compacta, SNC),
, , DA
. DA

393
, ,
DA Parkinson .

Parkinson

9.2

Parkinson.
,
.
Parkinson

DA
(corpus striatum): (putamen)
(caudate nucleus). DA ,
[18F]DOPA DA
, DA
Parkinson.

9.3 ,
[18F]DOPA DA
, Parkinson.

DA ,
, . 1988, McNeil
, ,
Parkinson.
DA ,
,
,
DA.

394

9.4 ,
Parkinson (McNeil, 1988).

,
Parkinson 1913, Frederick Lewy,

.

9.5 Frederick Lewy

5-25m
.

395
Lewy bodies, , (
) 5-25m
(, , -). Parkinson Lewy bodies.
Parkinson ,
,

Meynert. -
Parkinson.

Severe PD

Moderate PD

Normal

Severe PD

Moderate PD

Normal
Severe PD

Moderate PD

Normal

1960, Oleh Hornykiewicz

DA ,
Parkinson. ,
.
DA, (HVA).
Parkinson,
70-80% DA (Agid,
1987). , DA
.
DA. ,
DA HVA Parkinson , DA/HVA
.

9.6 H HVA ( DA) Parkinson

DA, DA/HVA
. Parkinson 70-80%
DA .

DA,
D1 D2,
. up-regulation
.

:

(caudate nucleus), (putamen) (globus pallidus).

396

(substantia nigra) (subthalamic nucleus).

9.7 :
, , , .

.
.
,
.

(corpus
striatum) (caudate) (putamen).
(input zone) .
,
,
input .
( )
(substantia nigra-pars compacta).

(caudate) (putamen) .

(caudate) (putamen) ,
.


sec .

397
GABA ,
:
.

9.8


GABA ,

:
.

,
.

398
, 100 . , 75%
. , ,
700.000 . , 100
.

(substantia nigra, pars reticulata) GABA
,
.

, .

(superior colliculus),
.
,
,
, . ,
.
, GABA-,
,
,
. deshinibited.

9.9 ( )
GABA , GABA ,
- .
, .

399

9.10
. ,
GABA
. ,
.

:

,

(direct pathway),
.
,
, (indirect pathway).
, ,
.
,
.
. ,
GABA . ,

400
,
.

DA

, output .
:
.

( ),
D1 ,


( ), D2
.
,
:

,

.

401
Parkinson,

. ,
, .
Parkinson, ,
: .
Parkinson
.
--.

9.11 .

PARKINSON
,

.
Parkinson
(-methyl-p-tyrosine) ,
ACh, 5-HT DA.
PD.
, L-DOPA, ,
PD .

.
Parkinson
(1-methyl-4phenyl-1,2,3,6-etrahydropyridine),
Parkinson,
. .
1976, , Barry Kidston, Bethesda, Meryland.

. , (1-methyl-4phenyl-

402
propriopiperidine), Hoffman-Laroche.
meperidine, .
Kidston
, . ,
.
. 3
.
, haloperidol
( D2), . ,
Kidston PD,
. L-DOPA,
.
Kidston P.
, .
,
. ,
.
Barry Kidston (
L-DOPA) , 1978 overdose .

, PD. ,
DA .
1982, .
PD. Santa Clara Valley
Medical Center, Stanford University Medical School, J.
Lanston, PD .
L-DOPA.

drug designer, Kidston,
MPPP. 1983, J. Lanston Science, Parkinson.
.

L-DOPA

1983,

Burns,
PD
,

, ,
, ,
.
L-DOPA.
,

DA
.

403

PD.

.
. , . PDP+ (1-methyl, 4-phenyl-1,2-dihyropyridinium ion) MPP+ (1methyl-4-phenyl-pyridinium ion).
+ , DA
-;
MAO-B , + ,
+ DA
DA. in vivo,
. + DA
(DAmato, 1986) .

9.12 ,
. - +,

. DA
Complex I .

, + ,
Complex I
(Tripton, 1993). ,

404
, ,
.

(, ) ,
. - ,
,
+
. ,
, +
.
PARKINSON
1. Stress
Parkinson
, ,
Parkinson.
DA
.
stress.
,
(2) (22) (reactive
oxyradicals, ROS): (2-) ()1.

9.13 (2)
(22) : (2-) ().

.
, .
1

405
: ,
, .
,
.
: (1) ,
C, ROS
, (2)
ROS.

9.14

.
(SOD, superoxide
dismoutase) 2- 22.
(GPx,
glutathione peroxidase)
22 2 2.

stress
:
1. 22 DA -.
, DA
22.

Dopamine

Cohen (1983)
stress Parkinson.
2. - -
(2).
(quinones), (22)
(ROS).
- DA
. , -
.

406

9.15 DA,
, 22 2- DA -, DA-
- DA.
.

3.
. ROS 22
Fenton.
Fe3+ Fe2+.

1984, Triggs Wilmore Fe2+ ,

.
, Fe3+ Fe2+,
Fenton.

stress Parkinson. ,
Parkinson,
postmortem (Jenner, 1992). ,
Parkinson (Gerlach, 1994). ,

Parkinson (Jenner, 1992).
, (Schapira, 1990 DiMauro, 1993)
complex I ,
Parkinson.

407
complex +
.

9.16 stress
. DA DHPA (3,4-dihydrphenylacetaldeyde) 22. 22
,
() Fe2+ ( Fenton).
Fe3+ Fe2+
.

2.
()

Parkinson.
, ,
.
: , Parkinson
(
1950)
( ).
4
Parkinson,

, Parkinson
80% .
Parkinson

D .

408
. ,
DA ,
.
( )
. stress
,
stress Parkinson. , Parkinson
.
, . ,
stress
Parkinson,
.
, . , stress
,
.

,
.

2.
1.
3.
4.

9.17 DA .
DA ,
80% DA Parkinson ( 60
). 1. Parkinson D . 2.
DA DA
. 3.
. 4. Parkinson
.

. 1876, Ordenstein
belladonna ( ) Parkinson
. , ,

409
. belladonna
. DA
ACh ,
,
outflow .

Amantadine

amantadine ,
. 1966,
. 1968, Schwab
Parkinson,
153 Parkinson
2/3 . amantadine
DA .

L-DOPA. 1958, o Carlsson

DA, L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine)
-Parkinson .
Parkinson.
L-DOPA DA
L- (DC).

9.18 . DOPA
DA L- .

AADC , , , ,
L-DOPA, ,
DA, .
carbidopa, ,
AADC, L-DOPA
.
- Parkinson,
L-DOPA, 50%

410
on-off,
, ,
.
L-DOPA,
80%
.
9.19 / L-DOPA
.
COMT (catechol-O-methyltransferase) AADC
(aromatic L-amino acid decarboxylase)
,
L-DOPA ,
.
(monoamine oxidase)
. b/
s
(selegiline rasagiline).

9.20 L-DOPA, DA
AADC. carbadopa, . L-DOPA
,
AADC DA. H DA -. -
- ( ) DA .

411
L-DOPA . LDOPA
. ,
. LDOPA ,
L-DOPA.
L-DOPA .
. s

. ,
,
L-DOPA (Kopin, 1993).
-, (-)deprenyl (
selegiline) ,
L-DOPA. selegiline LDOPA L-DOPA on-off
(Birkmayer et al, 1975). , Birkmayer
selegiline L-DOPA Parkinson.
rasagiline, -
Minnesota (Youdim, 2005).
selegiline
Parkinson (Mandel, 2005). Youdim (2005)
rasagiline, ,
, Ladostigil,
-, Parkinson .
COMT. COMT (entacapone, tolcapone)
L-DOPA.
, , , ,
.
. DA,

: , bromocriptine,
pergolide, lisuire, cabergoline, -, ropinirole, pramipexole,
apomorphine. DA
L-DOPA L-DOPA
.
(Schapira, 2003). ,
,
.
, , (Wong, 2003).
(iron chelators). , Lewy bodies.
stress, ,
- - ,
.
stress,
Parkinson. - (Zhang, 2005)

412
(desferoxamine V-28) .

.

9.21 - -,
stress ( )
- .
Lewy bodies.

C. C .

, B C,
L-DOPA 2,5 (Fahn, 1992).

. Parkinson,

.

.

1. .
,
.

413

,
.
.
Fred et al (1981):
. , .
2. .
.
1987
(Lindvall et al, 1989; Madazo et al, 1988).
100 .
,
, :
( - ,
5-9 ),
.
3. .

, .
xenografts,
. xenografts 1975,
(Travis, 1995).
.

DA, DA
Parkinson.
( ),
( ) DOPA,
BDNF (Brain derived neurotrophic factor),
.

(Sonntag, 2005).

,
, 90%
(Emgard, 2003).
4. .
.,
Parkinson,
.
Parkinson,
, DA,
.

DA .
DA in vivo,
.
,
,

414

.
Shen (2000) ,
(), L- (AADC) GTP
- (GCHI),
.
( 10 ). Jurraya (2009)
, .
,
2 44 . , Palfi
(2010) 6 Parkinson. 4 30%
2 . .
,
AADC ,
L-DOPA DA. ,
L-DOPA DA,
Parkinson, AADC
L-DOPA (Eberling, 2010).
, .

GDNF (Glial-derived neurotrophic factor),
.
GDNF ,

, (Wang,
2002). , - GDNF
Parkinson (Patel,
2005).

.
DNA
,
Parkinson.
DBS: Stimulation of deep brain structures.


, ,
Parkinson (Weaver, 2009). Benabid Grenoble,
1987,

(100-130Hz)

()
,
(Subthalamic nucleus,
SN) .
70.000
DBS ,

Parkinson. ;

415
1980,
,
Parkinson.
,
,
, .

,
Bergman
(1990)

-

.




(
)

-. 299 Parkinson,
24 (Follett, 2010).
DBS ,
<70 , ,
L-DOPA,
.
:
50 ,

Parkinson.

,
Nobel Arvid Carlson.
Parkinson

.
Arvid Carlsson Nobel 2000
25 1923 -

, 80% .
Parkinson
, ,
. ,
, , SPECT,
. , SPECT
DA , DA,
.