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21th century drugs. “Magic bullet” or “ Multitarget warhead”. S.B.Seredenin. The. Paul Ehrlich (1854-1915). The Nobel Prize in Physiology or Medicine 1908 "in recognition of their work on immunity”. Paul Ehrlich 1/2 of the prize Germany Goettingen University Goettingen, Germany; - PowerPoint PPT Presentation
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S.B.SeredeninState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
Paul Ehrlich (1854-1915)The Nobel Prize in Physiology or Medicine 1908"in recognition of their work on immunityThe Ilya Ilyich Mechnikov1/2 of the prizeRussia Institut Pasteur Paris, France
Paul Ehrlich1/2 of the prizeGermanyGoettingen University Goettingen, Germany; Knigliches Institut fr experimentelle Therapie (Royal Institute for Experimental Therapy) Frankfurt-on-the-Main, Germany
State Zakusov Institute of Pharmacology RAMS, Moscow
Afobazol : -000861 03.11.2005State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
Effect of emotional stress on the 3H-diazepam binding level in the brain membranes of MR & MNRA rats
Balb/cC57Bl/6Effect of emotional stress on the 3H-diazepam binding level in the brain membranes of Balb/c & C57Bl/6 miceMRMNRA* -
(CEREP, France)
1, A2A, A2B, A31, 2, 1, 2, 3 ( )BZDD1, D2S, D2L, D3, D4, D5 (- )GABAA, GABAB (1b) AMPA, Kainate, NMDA, Glycine (-), PCPH1, H2, H3, H4LPA1 (Edg-2)MT1, MT2, MT3 (ML2)M1, M2, M3, M4, M54 -BGTX- (42), 7 -BGTX-P2X, P2Yc5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4e, 5-ht5A, 5-HT6, 5-HT7 1, 2
(CEREP, France)
AT1, AT2CCK1, CCK2 CRF1GAL1, GAL2NK1, NK2, NK3 YY1, Y2 , NTS1 , 2 (Delta opioid receptor), (Mu opioid receptor) (sst )V1a, V1b, V2
(CEREP, France)
GRPR -(R)-- Ca2+ CaV1.1 (L-) K+ KIR6 (KATP) Cl- NBTI (NET)BTCP (DAT) (GAT) (CHT) (SERT)
CalmodulinK+IP3CaM-PKCell EffectsIP3CaCaCaCaIP3PIP2PLC
Voltage-gated Ca channelNMDA RCa + +Ca + + receptorIP3 receptorLipid raftCa ATPaseCa + +AnkyrinBiPDHEAK+ channelIP3RState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
[Melatonin]Cl-Cl-AfobazolGABA A R MT1 R3H-diazepam biding3H-diazepam biding- Melatonin- AfobazolState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
Control (Localization on endoplasmatic reticulum)
Afobazol (10-8) (Localization on plasma membrane in 60 min following Afobazol application)
sigma-receptorsImmunofluorescence staining
CalnexinSigma-receptor + CalnexinState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
Neuroprotective effect of Afobazol in HT-22 cell line exposed to oxidative stress
Application 24 h after H2O2Application 30 min before H2O2 Application right after H2O2Optical density Control 22 10-8 10-5 1,5 Optical density Control 22 10-8 10-5 1,5 Optical density Control 22 10-8 10-5 1,5 State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
0.4890.0335062183
0.36466666670.0532248897
0.5150.070953082
0.52342857140.0929206376
*
^
^
1
22, -5,24, -8,24,-5, 30 ,-8, 30
0.4870.3330.5020.4960.601
0.620.393
0.5310.6110.442
0.2920.5470.3880.527
0.4490.3840.480.634
0.4180.356
0.698
0.5520.4950.3560.633
0.5410.473
0.4870.490.4260.672
0.5840.4190.474
0.6080.3980.509
0.4890.36466666670.52342857140.5150.41422222220.5935
0.03350621830.05322488970.09292063760.0709530820.0462283650.0759786154
0.02451168960.01910358450.00365759410.09421813880.000943633
10074.574028107.0406105.3169784.70802121.37014 , %
^
1
0.4890.0335062183
0.36466666670.0532248897
0.52342857140.0929206376
0.5150.070953082
0.41422222220.046228365
0.59350.0759786154
*
^
^
^
HT-22, ,
2
22, -8,24, -5,24
0.4870.5020.333
0.62
0.5310.611
0.2920.547
0.4490.3840.48
0.418
0.4950.552
0.541
0.490.487
0.4190.584
0.608
0.4890.36466666670.5150.5234285714
0.03350621830.05322488970.0709530820.0929206376
0.02451168960.00365759410.0191035845
10074.574028105.31697107.0406 , %
6.85194210.88444614.50983219.002174
2210-8 M10-5 M
10074.574028121.3701484.70802af 10-8 30min beforeaf 10-5 30min before
6.85194210.88444615.5375489.453653275
control2210-8 M10-5 M
^
2
06.851942
010.884446
014.509832
019.002174
*
^
^
survival (% of control)
3
00.0335062183
00.0532248897
00.070953082
00.0929206376
*
^
^
22,-8, 30 ,-5, 30
0.4870.6010.496
0.393
0.5310.442
0.2920.5270.388
0.4490.3840.634
0.4180.356
0.698
0.6330.356
0.473
0.6720.426
0.474
0.5090.398
0.4890.36466666670.59350.4142222222
0.03350621830.05322488970.07597861540.046228365
0.02451168960.0009436330.0942181388
10074.574028121.3701484.70802 , %
6.85194210.88444615.5375489.453653275
2210-8 M10-5 M
1006.851942
74.57402810.884446
121.3701415.537548
84.708029.453653275
*
^
survival (% of control)
00.0335062183
00.0532248897
00.0759786154
00.046228365
*
^
2
0.4890.0335062183
0.36466666670.0532248897
0.59350.0759786154
0.41422222220.046228365
*
^
1
22, -5,24, -8,24,-5, 30 ,-8, 30
0.4870.3330.5020.4960.601
0.620.393
0.5310.6110.442
0.2920.5470.3880.527
0.4490.3840.480.634
0.4180.356
0.698
0.5520.4950.3560.633
0.5410.473
0.4870.490.4260.672
0.5840.4190.474
0.6080.3980.509
0.4890.36466666670.52342857140.5150.41422222220.5935
0.03350621830.05322488970.09292063760.0709530820.0462283650.0759786154
0.02451168960.01910358450.00365759410.09421813880.000943633
10074.574028107.0406105.3169784.70802121.37014 , %
^
1
0.4890.0335062183
0.36466666670.0532248897
0.52342857140.0929206376
0.5150.070953082
0.41422222220.046228365
0.59350.0759786154
*
^
^
^
HT-22, ,
2
22, -8,24, -5,24
0.4870.5020.333
0.62
0.5310.611
0.2920.547
0.4490.3840.48
0.418
0.4950.552
0.541
0.490.487
0.4190.584
0.608
0.4890.36466666670.5150.5234285714
0.03350621830.05322488970.0709530820.0929206376
0.02451168960.00365759410.0191035845
10074.574028105.31697107.0406 , %
6.85194210.88444614.50983219.002174
2210-8 M10-5 M
10074.574028121.3701484.70802af 10-8 30min beforeaf 10-5 30min before
6.85194210.88444615.5375489.453653275
control2210-8 M10-5 M
^
2
06.851942
010.884446
014.509832
019.002174
*
^
^
survival (% of control)
3
00.0335062183
00.0532248897
00.070953082
00.0929206376
*
^
^
22,-8, 30 ,-5, 30
0.4870.6010.496
0.393
0.5310.442
0.2920.5270.388
0.4490.3840.634
0.4180.356
0.698
0.6330.356
0.473
0.6720.426
0.474
0.5090.398
0.4890.36466666670.59350.4142222222
0.03350621830.05322488970.07597861540.046228365
0.02451168960.0009436330.0942181388
10074.574028121.3701484.70802 , %
6.85194210.88444615.5375489.453653275
2210-8 M10-5 M
1006.851942
74.57402810.884446
121.3701415.537548
84.708029.453653275
*
^
survival (% of control)
00.0335062183
00.0532248897
00.0759786154
00.046228365
*
^
1
0.35771428570.0815673838
0.2823750.0746705861
0.3860.1006950843
0.36160.1073117991
*
^
^
1
22.-5.-8
0.2750.1740.204
0.350.3660.2940.468
0.3150.4780.287
0.5170.2490.3530.299
0.3820.2290.3440.483
0.2880.3980.2490.383
0.3770.3120.3210.255
0.2930.3850.539
0.2380.4220.321
0.5660.439
0.35771428570.2823750.36160.386. .
0.08156738380.07467058610.10731179910.1006950843..
0.04223508860.04799798610.0154201979.
10078.938761101.08634107.90743 , %
2
22.-8.-5
0.2750.1740.204
0.350.3660.4680.294
0.3150.2870.478^
0.5170.2490.2990.353
0.3820.2290.4830.344
0.2880.3980.3830.249
0.3770.3120.2550.321
0.2930.5390.385
0.2380.3210.422
0.4390.566
0.35771428570.2823750.3860.3616. .
0.08156738380.07467058610.10069508430.1073117991..
0.04223508860.01542019790.0479979861.
10078.938761107.90743101.08634 , %
22.80229420.8744928.14957429.99937..
^
H2O210-8 M10-5 M
*
2
022.802294
020.87449
028.149574
029.99937
^
^
*
,
(% )
1
3
00.0815673838
00.0746705861
00.1006950843
00.1073117991
*
^
^
Protective effect of the Afobazol against glutamate toxicity in hippocampal cell culture HT-22 (MTT assay)
Controlglutamate5mM10-8 M
10-5 M24 h before glutamateAfter glutamateAfobazolControlglutamate5mM
11624hAfobazol (10-8 )Afobazol was able to prevent cell damage in concentrations which were defined in brain after systemic administration State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
10023.249948
74.00204721.363358
91.70931423.092322
71.48413512.662027
*
^
survival (% of control)
1
.-.-5.-8
82424
0.2570.2230.174
0.160.281
0.2330.2430.1670.157
0.1350.1430.208
0.1750.1270.1430.164
0.3120.1140.199
0.230.1750.286
0.2140.1560.195
0.145
0.2330.277
0.211
0.244250.180750.17460.224
0.05678834970.05218031920.03092715460.0564033096
0.04091456640.37961484960.0734478609.
10074.00204771.48413591.709314 , %
2
.-.-8.-5
82424
0.2570.2230.174
0.160.281
0.2330.2430.1570.167
0.1350.2080.143
0.1750.1270.1640.143
0.3120.1140.199
0.230.2860.175
0.2140.1950.156
0.145
0.2770.233
0.211
0.244250.180750.2240.1746
0.05678834970.05218031920.05640330960.0309271546
0.04091456640.07344786090.3796148496.
10074.00204791.70931471.484135 , %
23.24994821.36335823.09232212.662027
2
10023.249948
74.00204721.363358
91.70931423.092322
71.48413512.662027
*
^
,
(% )
2
3
10023.249948
74.00204721.363358
91.70931423.092322
71.48413512.662027
*
^
survival (% of control)
MBD00162AB2.xls
9
0.244250.0567883497
0.180750.0521803192
0.17460.0309271546
0.2240.0564033096
0.24658333330.0336265231
*
^
^
-, , , -1, -22
1
comtrolglut.acidgk-2-5,gagk-2-8,gagk-1+gk2,-5
0.2540.2160.2170.243.--2,-5-2,-8Mix-5
0.2630.2120.1520.1480.219
0.2280.1920.1590.1540.184
0.2290.1880.2860.198
0.1980.1850.1580.1230.18
0.260.2170.1610.2030.232
0.2250.1480.1430.202
0.1010.1550.1960.171
0.1620.1760.1350.182
0.150.1440.1180.158
0.2050.146
0.23866666670.18133333330.17818181820.16190909090.1967777778
0.02507322610.0388908730.04260473730.03495841690.0290033523.
0.00364291020.43305228450.12751771650.1768843201.
1
0.0250732261
0.038890873
0.0426047373
0.0349584169
0.0290033523
*
-, , -22
2
.-.-5.-8-1, -5
8242424
0.2570.2230.1740.28
0.160.2810.22
0.2330.2430.1670.1570.187
0.1350.1430.2080.227
0.1750.1270.1430.1640.3
0.3120.1140.1990.225
0.230.1750.2860.27
0.2140.1560.1950.2
0.1450.252
0.2330.2770.284
0.2110.249
0.265
0.244250.180750.17460.2240.2465833333
0.05678834970.05218031920.03092715460.05640330960.0336265231
0.04091456640.37961484960.07344786090.0016398198.
2
0.0567883497
0.0521803192
0.0309271546
0.0564033096
0.0336265231
*
^
^
-, , , -1, -22
3
1
10011.825332
89.27426510.53573625
100.362987.8849643
102.3733510.43640477
101.4194311.5059678
^
^
^
survival (% of control)
1
. -
1 16 20
0.347
0.3890.4580.444
0.3630.4060.4210.4690.406
0.4690.4010.4170.424
0.4430.380.408
0.367
0.291
0.362
0.3850.4370.459
0.4580.3880.4570.489
0.3680.3380.375
0.422
0.41333333330.3690.41483333330.42314285710.4192 .
0.04887807960.0435476750.03259089850.04313710150.0475579646..
0.06406809930.03297009790.03257783540.0593190664.
10089.274265100.36298102.37335101.41943 , %
2
. - 1 16 20
0.347
0.3890.4580.444
0.3630.4060.4210.4690.406
0.4690.4010.4170.424
0.4430.380.408
0.367
0.291
0.362
0.3850.4370.459
0.4580.3880.4570.489
0.3680.3380.375
0.422
0.41333333330.3690.41483333330.42314285710.4192 .
0.04887807960.0435476750.03259089850.04313710150.0475579646..
0.06406809930.03297009790.03257783540.0593190664.
10089.274265100.36298102.37335101.41943 , %
11.82533210.535736257.884964310.4364047711.5059678..
^
2
10011.825332
89.27426510.53573625
100.362987.8849643
102.3733510.43640477
101.4194311.5059678
^
^
^
,
(% )
2
3
10011.825332
89.27426510.53573625
100.362987.8849643
102.3733510.43640477
101.4194311.5059678
^
^
^
survival (% of control)
MBD0016FBB3.xls
3
0.41333333330.0488780796
0.3690.043547675
0.41483333330.0325908985
0.42314285710.0431371015
0.41920.0475579646
^
^
^
-, , , -22.
1
.-.-
1 30 30 1
0.3520.2970.3460.3390.271
0.360.3510.3950.388
0.3430.351
0.3730.4010.334
0.3790.3870.3760.397
0.3660.3880.4520.332
0.3420.3450.337
0.4470.3440.4220.3220.409
0.3780.3570.3560.3930.399
0.3730.3680.3920.3610.437
0.3950.3460.3560.368
0.3790.366
0.37840.35580.37988888890.35527272730.3835 0.37840.3589090.3586670.37310.370429
0.02831646560.02601623420.03881186820.02518765930.0576393962. .
0.03976137050.06346976040.48143516650.1020633758
&A
&P
1
0.0283164656
0.0260162342
0.0388118682
0.0251876593
0.0576393962
*
-, , -22,
2
. -
1 16 20
0.347
0.3890.4580.444
0.3630.4060.4210.4690.406
0.4690.4010.4170.424
0.4430.380.408
0.367
0.291
0.362
0.3850.4370.459
0.4580.3880.4570.489
0.3680.3380.375
0.422
0.41333333330.3690.41483333330.42314285710.4192 .
0.04887807960.0435476750.03259089850.04313710150.0475579646..
0.06406809930.03297009790.03257783540.0593190664.
&A
&P
2
0.0488780796
0.043547675
0.0325908985
0.0431371015
0.0475579646
&A
&P
^
^
^
-, , , -22.
3
&A
&P
4
&A
&P
5
&A
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6
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7
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8
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&P
9
&A
&P
10
&A
&P
11
&A
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12
&A
&P
13
&A
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14
&A
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15
&A
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16
&A
&P
Increase in Nerve growth factor (NGF) content 6 hours following Afobazol (10-8 ) application Western blot analysis 1 2 3 4 5 6 7 Control Afobazol NGF (10-8 ) NGFDensitometric units Densitometric analysis of the above Western blot ControlAfobazol*State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
2
0.90.2645751311
1.23333333330.0577350269
*
1
0.71.2
1.21.3
0.81.2
0.91.2333333333 .
0.26457513110.0577350269. .
0.0499909834.
1
00.2645751311
00.0577350269
*
NGF 6 HT-22.
2
1.71.5
1.21.4
1.4
1.451.4333333333 HSP32 6
3
Concentration-dependent effect of Afobazol upon BDNF content in hippocampal cell line -2210-1110-710-610-510-1010-910-8CState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
0.276342017
0.2613056476
0.3007634942
0.3156745706
0.3446396924
0.3205262568
0.334576634
0.3010756969
***
*
*
**
BDNF/protein, pg/mkg
1
10-11 10-10 10-9 10-8 10-7 10-6 10-5
0.28041356850.25814378150.29212628790.34340854320.31461036590.3392783065
0.27735990490.29164450550.30475548040.28928109050.34587084160.33391917650.37506715740.2988965156
0.27125257770.30475548040.3192008250.28831751730.31569976950.3032548783
0.2524975920.30823939560.34377899470.3064367728
0.26040225720.32914288660.35168510820.32200522950.3653831154
0.24384010150.26556143460.30253125860.3055946822
0.2763420170.26130564760.30076349420.31567457060.34463969240.32052625680.3345766340.3010756969.
0.00466454820.01812378930.0210092230.02694782450.00174110790.02118164380.03032744250.0030818278.
Mean 1Mean 2pValid N1Valid N2Std.Dev.1Std.Dev.2
1 20.2763420170.3010756969
****Size of the brain infarct zone after the middle cerebral artery occlusion in rats Control 1,0 mg/kg 0,1 mg/kg 0,05 mg/kg AfobazolState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
11.11.21.2
4.61.181.18
4.80.870.87
11.290.970.97
% infarct zone
1
1 /0,1 /0,05 /
12.144.913.5512.166.265.8911.14.64.811.29
0.981.130.772.011.261.161.21.180.870.97
1
1.21.2
1.181.18
0.870.87
0.970.97
%
2
3
MBD0015F6AE.xls
1
12.140.980.98
4.911.131.13
3.550.770.77
%
1
1 /0,1 /0,05 /
12.144.913.5512.166.265.8911.14.64.811.29
0.981.130.772.011.261.161.21.180.870.97
1
00.980.98
01.131.13
00.770.77
%
2
02.012.01
01.261.26
01.161.16
%
3
01.21.2
01.181.18
00.870.87
00.970.97
%
Afobazol increase survival following the hemorrhagic stroke in ratsState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
01700
01008
01100
02500
05008
*
#
insult + Afobazol (1,0)
sham-operated
insult
insult + Afobazol (0,1)
+ (1,0)
+ (0,1)
days
% of the lost animals
1
00000
1710112550
00000
08008
13714
1
*
#
+ (1,0)
+ (0,1)
%
2
3
Effect of Afobazol on the severity of neurological deficits in rats after hemorrhagic stroke (McGrows scale)
1 - Flabbiness, motor slowing2 weakness in extremities3 manege locomotion4 paresis of 1-4 extremitiesState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
401006045
25904036
0401027
0401010
sham-operartedstrokestroke+afobazol (1,0)stroke+afobazol (0,1)
+ (1,0)
+ (0,1)
Symptoms
%
1
00000
1710112550
00000
08008
13714
1
*
#
+ (1,0)
+ (0,1)
%
2
402500
100904040
60401010
45362710
1 - ,
2 -
3 -
4 - 1-4
2
+ (1,0)
+ (0,1)
%
6
5
95696276
30261413
146105128110
97703925
13714
5
*
#
#
#
#
#
+ (1,0)
+ (0,1)
4
12482920
+ (1,0) + (0,1)
*
4
*
#
#
()
3
32241521
117129
21201715
33232337
13714
3
*
#
#
*
#
#
#
*
#
+ (1,0)
+ (0,1)
Ladasten : -010257/08State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
(CEREP, France)
1, A2A, A2B, A31, 2, 1, 2, 3 ( )BZDD1, D2S, D2L, D3, D4, D5 (- )GABAA, GABAB (1b) AMPA, Kainate, NMDA, Glycine (-), PCPH1, H2, H3, H4LPA1 (Edg-2)MT1, MT2, MT3 (ML2)M1, M2, M3, M4, M54 -BGTX- (42), 7 -BGTX-P2X, P2Yc5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4e, 5-ht5A, 5-HT6, 5-HT7 1, 2
(CEREP, France)
AT1, AT2CCK1, CCK2 CRF1GAL1, GAL2NK1, NK2, NK3 YY1, Y2 , NTS1 , 2 (Delta opioid receptor), (Mu opioid receptor) (sst )V1a, V1b, V2
(CEREP, France)
GRPR -(R)-- Ca2+ CaV1.1 (L-) K+ KIR6 (KATP) Cl- NBTI (NET)BTCP (DAT) (GAT)
Genes and proteins regulated by Ladastenaldolase A GAPDH Hsp70 CCTe VCP proteosoma 26S clathrin LCA tubulin alpha 6 alpha internexin CRMP-2 neuronal protein 22
State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
2
2
2
5
glycolytic proteins
stress proteins
protection proteins
synaptic proteins
1
- 2
2
2
5
1
2
3
1
2
2
2
3
1
5
4
4
glycolytic gene
Ca signaling
Onco-suppressors
neuropeptides, extracellular secreted proteins
membrane transporter genes
synaptic function genes
neurogenesis
matrix adhesion receptors, cell-cell adhesion receptors, plasma membrane protein
1
2
2
2
3
1
5
4
4
1
2
3
Schematic rate of methylation 376 b.p. 5'-flanking region of tyrosinehydroxylase gene (-292 - +84) of rat brain hypothalamusLadastenControlState Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
1
0.90.8460.07276068750.0875429306
10.38500.1180166987
0.7270.2310.10804982510.1022220766
0.8180.4620.09358104380.1209170839
10.7500.1050210063
10.61500.1180166987
0.9090.5380.06975545520.1209170839
0.9170.9170.0669112670.066911267
10.84600.0875429306
10.93200.0610573501
1100
0.8330.4620.09045993590.1209170839
10.46200.1209170839
0.750.5380.10502100630.1209170839
0.9170.6920.0669112670.1119705844
10.84600.0875429306
0.9170.6670.0669112670.1143037748
CpG-nucleotides localisation
mean rate of methylation
%
19999
298100
39898
49899
598100
69699
710097
891100
995100
1095100
1198100
1210099
1398
97.166666666799.1538461538
. 2.55247948380.9870962336
1.44417468520.536581765
2.55247948382.5524794838
0.98709623360.9870962336
,
c.. .. (p)
-2690.90.072760687590.8460.0875429306110.9180120.90.846
-22810110.3850.118016698750.01581910.385
-2250.7270.108049825180.2310.102222076630.0716110.7270.231
-2180.8180.093581043890.4620.120917083960.2883830.8180.462
-15610120.750.105021006380.04844710.75
-14310110.6150.118016698780.19378910.615
-1400.9090.0697554552110.5380.120917083970.0928150.9090.538
-1340.9170.066911267110.9170.066911267111.0626090.9170.917
-11710120.8460.0875429306110.5210.846
-9510120.9320.0610573501121.0410.932
-8210121013211
-430.8330.0904599359100.4620.120917083960.1266930.8330.462
-1910120.4620.120917083960.0071410.462
-80.750.105021006390.5380.120917083970.4962710.750.538
150.9170.066911267110.6920.111970584490.3714290.9170.692
4910120.8460.0875429306110.5210.846
570.9170.066911267110.6670.114303774880.1937890.9170.667
double single sided
0.07276068750.07276068750.08754293060.0875429306
000.11801669870.1180166987
0.10804982510.10804982510.10222207660.1022220766
0.09358104380.09358104380.12091708390.1209170839
000.10502100630.1050210063
000.11801669870.1180166987
0.06975545520.06975545520.12091708390.1209170839
0.0669112670.0669112670.0669112670.066911267
000.08754293060.0875429306
000.06105735010.0610573501
0000
0.09045993590.09045993590.12091708390.1209170839
000.12091708390.1209170839
0.10502100630.10502100630.12091708390.1209170839
0.0669112670.0669112670.11197058440.1119705844
000.08754293060.0875429306
0.0669112670.0669112670.11430377480.1143037748
State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
Ladasten inhibits GABA transporter gene expressionLADASTENhouse-keeping genetarget gene
Ladasten decrease the amount of IL-1 (CEREP, France)IL-1 hypersomnia
exhaustion
suppress appetite
decrease physical activity resistance
activation hypothalamus-hypophysis axis
increase catecholamines release depression like symptoms
decrease exploratory behavior
State Zakusov Institute of Pharmacology RAMS, Moscow
State Zakusov Institute of Pharmacology RAMS, Moscow
* +