![Page 1: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/1.jpg)
Ru-Band Lu, MD.Shiou-Lan Chen, PhD.
National Cheng Kung University
Neuro-degeneration and
Novel Treatment in Heroin dependence
![Page 2: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/2.jpg)
Neurodegeneration in Mental Illnesses
• Schizophrenia
• Bipolar disorders
• Substance use disorders (alcohol)
• Anxiety disorders?
• Personality disorders?
2
![Page 3: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/3.jpg)
Neuronal degeneration in schizophrenia
Schizophrenia and bipolar disorders
– Decreased gray & white matter and lateral ventricular dilatation (Largen et al., 1984; De Peri l et al., 2012)
3
![Page 4: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/4.jpg)
Neuronal degeneration in Bipolar Disorder (BP)
• Diffused gray and white matter loss, enlarged ventricles & mild prefrontal volume loss. (Wilde, et al., 1985)
• 17% larger lateral ventricles and 2.5 times in deep white matter hyperintensities. (Kempton, M.J., et al., 2008.)
4
![Page 5: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/5.jpg)
MRI in middle-aged women
Neuronal degeneration in Substance Abuse
5
![Page 6: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/6.jpg)
Neuronal degeneration in substance use?
Animal studies
•Opioid use – Reduction dopaminergic neurons in ventral tegmental area (VTA) of rats (Chu, 2008)
•Heroin and cocaine use– Showing neurotoxicity in rat (Cunha-Oliveira et al., 2010)
•Alcohol use– Reduced hippocampal neurogenesis
– Impaired long-lasting memory in monkey (Taffe, 2010).
6
![Page 7: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/7.jpg)
Treatment of Neurodegeneration disease
• Current therapy treating symptoms, but few slowing or inhibiting the progress
• Without treatment in heroin dependence
• Development of novel therapy for central, peripheral degeneration illness
7
![Page 8: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/8.jpg)
Microglia
Source for
neurotrophin production
Target for
anti-inflammation
Astroglia
Glial cells : Key roles in disease and prime targets for therapy
8
![Page 9: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/9.jpg)
9
Hypothesis
1.Neuronal
Degeneration
2.White/Gray Matter Damage
Causing/Onset/Relapse of Mental Illness
The activation of Neuro-immune system
BrainBlood
Blood-Brain-Barrier
CytokinesCytokines
![Page 10: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/10.jpg)
Qin et al. (2007)
0
20
40
60
80
100
120
0 .5h 1h 2h 3h 6h 9h 7 m 10 m
TN
F
(%
of
pea
k)
Time
A single IP LPS injection induced TNF-α production both in peripheral and brain in rat
Liver**** **
**
**
**
Brain** **
**** ****
**
**
Blood**
**
**
**
TNF-
LPS
Kupffer cell
![Page 11: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/11.jpg)
Role of microglia in toxin-induced progressive neurotoxicity
Pro-inflammatory
Factors (ROS, NO., TNFa, IL-1,
PGs)
Reactive Microgliosis
(Self-propelling)
LPS (Extra Neurotoxin)
Ac
tiva
tio
n
MPTP (Intra Neurotoxin)
Microglia
(Working Model)
Dopaminergic
Neuronal Damage
11(Hong et al., 2005)
![Page 12: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/12.jpg)
NADPH oxidase (PHOX)
Activated
O2O2 • –
NADPH NADP+ + H +
Resting
gp91
p22rap1a
p40
p47rac2
p67
MAC-1
LPS
out
in
PKC
P
P
Naloxone,Dextromethorphan
Memantine
12(Hong et al., 2005)
![Page 13: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/13.jpg)
Transfection of gp91PHOX, a membrane subunit of PHOX,
increases [3H]-naloxone binding
0
100
200
300
[3H]-(-)-Nal
Bin
din
g C
ap
acit
y (
% W
T)
WT
[3H]-(+)-Nal
*
Gp91-transfected
400COS-7 Cells (WT)
Ligand Binding Assay
StableTransfectio
n
COS-7 gp91
(gp91)
gp91
*
13(Hong et al., 2007)
![Page 14: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/14.jpg)
O2
O2 • –
Dual Functions of Superoxide Radicals
gp91
Microglia
MAC1
TLR4LBP
CD14
PHOX
ROS
H2O2
O2 • –
TNF- IL-1
NO •
ONOO -
2) Gene Expression
1) Neurotoxicity
NF-kB,AP-1
PKCLPS
LPS
DA neurons 14(Hong et al., 2005)
![Page 15: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/15.jpg)
15
Memantine
• An non-comparative NMDA receptor, medication for Alzheimer's disease (20 mg/day)
• Low dosage having neuroprotective effects in vitro and in vivo (Wu et al., 2009)
![Page 16: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/16.jpg)
LPS
Microglia
TNF-aIL-1b
Neuronal death
ONOO-
NO • O2 • -
Conventional Regimen:
• Aspirin, COX 2 inhibitors (PG)
• Anti-oxidants (Free radicals)
• Antibodies (TNF-α, IL-1)
• Receptor antagonists (TNF-α)
• Cortisone (toxic for long-term use)
Novel Strategy: Modulation of microglial activity
•Morphinans : Naloxone, D-Morphine
Dextromethorphan
•Dynorphins, Enkephalin, PACAP
•Memantine
Novel anti-inflammatory therapy
PG’s
16
(Hong et al., 2005)
![Page 17: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/17.jpg)
Memantine
LPS
Dopaminergic Neuron
ONOO-
TNFαIL-1β
NO O2 • -
Microglia
PHOX
Inhibition of microglial PHOX (by binding to gp 91) is
associated with DM-, Memantine-elicited neuroprotective effect
17(wu et al., 2009)
![Page 18: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/18.jpg)
18
Mechanism underlying Memantine induced increase in expression of neurotrophic factors in astroglia
HDACHATs
Astroglia
Memantine
mRNA of GDNF, BDNF
GDNF, BDNF
Nuclear
(Chen et al., 2009)
![Page 19: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/19.jpg)
LPS
Acti
vati
on
Trophic factors:(GDNF, BDNF, NGF)
Pro-inflammatory factors: Superoxide, iROS NO, TNF, PGE2
Reactive Microgliosis
Astroglia
Microglia
DA neuron
Inhibition
Memantine
Stimulation
Memantine
Combined therapy for neurodegenerative diseases
(Self-propelling)
Neurogenesis
19(wu et al., 2009)
![Page 20: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/20.jpg)
Hypotheses & Experimental Protocol in Human
• Neuro-inflammation inducing heroin dependence and progressive neurodegeneration
• Heroin dependence and neurondegeneration causing progression of heroin use, mental illness
20
![Page 21: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/21.jpg)
Cytokines v.s. Substance Use in Animal
• Opioid
– Increased IL-1β, and IL-6 in vitro. (Kapasi, 2000) – Increased iNOS and cytokines in the locus coeruleus (Dyuizen I et al., 2009)
• Alcohol – Increased microglia in cerebellar and hippocampal of the rat . (Riikonen, 2002)
– Downregulated in the neocortex, hippocampus, and cerebellum of rats and conversed by COX-2. (Pascual et al., 2007)
• Methamphetamine – Increased free radical & overactivity of cytokines. (Imam, 2001)
21
![Page 22: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/22.jpg)
Research Aims
• Analysis of plasma cytokine and BDNF levels– Cytokines and BDNF: through BBB (Pan et al., 1998)
– BDNF: a neuro-degeneration biomarker (Laske et al. 2006)
– Cytokines: an neuro-inflammation biomarker (Buckley, 2007)
• The relationship of plasma cytokine, BDNF levels with heroin dependence
• Using effective drugs in neuroprotective and neurogenesis
22
![Page 23: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/23.jpg)
23
Human-
Heroin dependence treatment
![Page 24: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/24.jpg)
Methods
• Methadone maintaining treatment
• Adjustment the methadone dosage
• Memantine (5mg/day) or placebo
• Measuring methadone plasma level weekly
• Measuring BDNF, cytokines (pre- & post-treatment)
24(Chen et al., submitted 2013)
![Page 25: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/25.jpg)
Results
• Longer of years of heroin use ( 5 years, n = 57 or 6 years, n = 58)
– lower TGF-β1 and BDNF levels
– Higher MTD (methadone) dosage
• Compared to healthy controls at baseline
– Higher plasma TNF-, CRP, IL-1β, IL-6, and IL-8 levels
– Lower plasma TGF-β1 and BDNF levels25
(Chen et al., submitted, 2013)
![Page 26: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/26.jpg)
Correlation of heroin used period with plasma
MTD dose, cytokines and BDNFat baseline
Heroin used years vs
MTD dose IL-8 TGF-β1 BDNF
Spearman r 0.203 -0.083 -0.212 -0.255
95% confidence interval
0.003 to 0.388 -0.276 to
0.116
-0.396 to -
0.013
-0.430 to -
0.061
P value (two-
tailed)
0.0404 0.3988 0.0321 0.0087
26
MTD, methadone; transforming growth factor (TGF)-β1; A non-parametric analysis
(Chen et al., 2013)
![Page 27: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/27.jpg)
Plasma cytokine, and brain-derived neurotrophic factor
baseline data Heroin-dependent Patients p-value
Healthy Controls
MTD+Placebo MTD+Mem
n = 72 n = 57 n = 58
Gender (F/M) 10/62 10/47 10/48 0.817
Age (years) 31.64 ± 0.72 37.53 ± 0.93*** 37.24 ± 0.94*** < 0.0001
Heroin use (years) - 7.49 ± 0.49 8.36 ± 0.97 0.492
MTD dose (mg) - 36.23 ± 2.96 36.18 ± 2.70 0.991
Plasam TNF- (pg/mL) 1.57 ± 0.20 3.74 ± 0.47*** 3.62 ± 0.34*** < 0.0001
Plasma CRP (ng/mL) 1.66 ± 0.17 4.38 ± 0.44*** 3.60 ± 0.38*** < 0.0001
Plasma IL1- (pg/mL) 0.54 ± 0.09 1.42 ± 0.28** 1.97 ± 0.27*** < 0.0001
Plasma IL-6 (pg/mL) 1.23 ± 0.13 2.47 ± 0.35** 2.42 ± 0.28** 0.0004
Plasma IL-8 (pg/mL) 1.38 ± 0.28 4.66 ± 0.56** 6.53 ± 1.24*** < 0.0001
Plasma TGF-1 (ng/mL) 32.27± 2.0 24.16 ± 2.22** 23.02 ± 2.00** 0.0023
Plasma BDNF (ng/mL) 20.0 0 ± 1.09 11.40 ± 1.18*** 9.55 ± 0.83*** < 0.0001
27Mem, memantine; MTD, methadone; TGF, transforming growth factor One-way ANOVA for comparing cytokines and BDNF; age was used as a covariate.
(Chen et al., submitted 2013)
![Page 28: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/28.jpg)
Results
After the 12-week treatment, compared with
baseline
•MTD (methadone) +Placebo group
– Increasing percentage of MTD dose after 4-week
•MTD+MM (memantine) group
– No change in MTD dosage
28(Chen et al., submitted 2013)
![Page 29: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/29.jpg)
Heroin dependence treatment Methadone + Memantine (5 mg/placebo)
29(Chen et al., 2012)
![Page 30: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/30.jpg)
Results
After the 12-week treatment, compared with both groups at baseline
•MTD with Placebo group
– No change in TNF- and IL-6, and BDNF levels
•MTD+MM group
– Decreasing TNF-, , IL-1β, IL-6 and IL-8 levels
– Increased tendency in BDNF level
30
(Chen et al., submitted, 2013)
![Page 31: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/31.jpg)
Heroin dependence treatment Methadone + Memantine (5 mg/placebo)
31(Chen et al., 2012)
![Page 32: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/32.jpg)
Heroin dependence treatment Methadone + Memantine (5 mg/placebo)
32(Chen et al., 2012)
![Page 33: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/33.jpg)
Comments
• Longer heroin use (including MTD) increasing
inflammation and neurotrophic dysfunction.
• MTD with memantine treatment decreasing MTD-
induced inflammation and neurotrophic dysfunction
• MM inhibiting the tolerance for MTD
• MM decreasing cytokines & increasing BDNF levels
33
![Page 34: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/34.jpg)
Comments
• Low dose Memantine– 5 mg/day of MM plasma level 10-50 ng/ml (0.05-0.2 M)
– No effect in NMDA receptor antagonist (IC50: 2-3 M)
(Parsons et al. 1999)
– Effective in heroin dependence treatment
– Benefit in neuron protect & decreasing neurodegeneration
34
![Page 35: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/35.jpg)
Conclusions
• Over inflammation correlation with neurodegeneration, heroin
dependence & mental illness
• Treatment symptoms and treatment progress
• Regulation autoimmune & neuron (cell) protection or genesis,
benefits from central to peripheral
• New effective drugs & the novel treatment model breaking
through the difficulty of new drugs development
• Inhibiting the tolerance of heroin dependence, one of important factors
of substance dependence 35
![Page 36: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/36.jpg)
Future Studies
• Treatment neuronal (cell) degeneration and developing
novel treatment in animal and human
• Developing related gene with the treatment effects
& predicted treatment response in central and
peripheral diseases
36
![Page 37: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/37.jpg)
Acknowledgement
• Professor Jau-Shyong Hong, PhD.• Professor Pao-Luh Tao, PhD.• Hung-Ming Wu, MD. PhD.• Shiou-Lan Chen, PhD.• Shih-Heng Chen, PhD.• Chun-Hsien, Chu, PhD.• Kuei-Ying Hsu, MS.• Chen-Lin Wang, MS.• Yu-Ting Hung, BD.• Mei-Chun Wen, BD.• En-Jhen Chang, BD.
37
![Page 38: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/38.jpg)
Thank you38
![Page 39: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/39.jpg)
39
![Page 40: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/40.jpg)
Potential beneficial effects of anti-inflammation-related drugs
• Addiction – Opiate abuse– Alcohol abuse – Smoking – Compulsive eating
disorder
• CNS diseases– Bipolar disorders– Depression– Schizophrenia– Alzheimer’s dis.– Brain ischemia – Parkinson’s dis.– MS – Spinal injury
• Peripheral diseases– Asthma– Arthritis – Arteriosclerosis– Cancer– Diabetes – Heart attack– Hepatitis – Inflammatory pain– Crohn’s dis. – Lupus – Sepsis
(endotoxemia)
40
![Page 41: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/41.jpg)
Human peripheral effect
41
![Page 42: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/42.jpg)
The lipid-rich atherosclerotic lesions were
identified with Oil-Red-O staining.
Dextromethorphan (DM) decreases high lipid diet-induced atherosclerotic lesion formation in apo-E-deficient mice
PBS 5 10 20 400
5
10
15
20
25
* *
*
DM (mg/kg)
Le
sio
n a
rea
(%
)
Control DM(10mg/kg)
DM(20 mg/kg) DM(40 mg/kg)
(Liu et al. 2009)
42
![Page 43: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/43.jpg)
6.0
7.0
8.0
9.0
5.0
4.0
3.0
Placebo
DM
*
†
‡
0 3 6Time (months) after DM (60 mg/tablet, bid)
Flo
w m
edia
ted
dil
ata
tio
n r
atio
Clinical trial of dextromethorphan (DM) in heavy smokers
CR
P l
evel
s (m
g/d
l )
Time (months) after DM (60 mg/tablet, bid)
1
2
3
45
6
7
8
9
10
0 1 2 3 6
*
*
Placebo
DM
* *
Blood flow-mediated dilatation ratio C-reactive protein (CRP)
(Liu et al.)
43
![Page 44: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/44.jpg)
Clinical trial of naltrexone in alcoholics
44(Chen et al., 2012)
![Page 45: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/45.jpg)
Neurotrophic and neuroprotective effects of memantine
H.M. WU, H.L. CHEN, N.S. TZENG
J.S. HONG, R.B. LU* (2009)
45
![Page 46: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/46.jpg)
Memantine has neurotrophic and neuroprotective effects to dopaminergic neurons
and against LPS-induced neurotoxicity46(Wu et al., 2009)
![Page 47: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/47.jpg)
The neurotrophic effect of memantine is astrocyte-dependent.
47(Wu et al., 2009)
![Page 48: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/48.jpg)
Memantine decreases the levels of pro-inflammatory factors induced by LPS. 48
(Wu et al., 2009)
![Page 49: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/49.jpg)
Memantine has independent neuroprotective effects on LPS-induced
neurotoxcity.
49(Wu et al., 2009)
![Page 50: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/50.jpg)
Memantine attenuates LPS-induced morphological activation of
microglia. 50(Wu et al., 2009)
![Page 51: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/51.jpg)
In Summary
Pro-inflammatory Factors
Reactive Microgliosis
(Self-propelling)
Microglia
Neurons Trophic
factors:(GDNF, BDNF,
NGF)Neurogenesis
Astroglia(1)
(2)
(-)
Anti-inflammat
ion
Neuro-protection
Neuronalgenesis
(+)
51
![Page 52: Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence](https://reader035.vdocuments.mx/reader035/viewer/2022070307/551b221955034607418b5b73/html5/thumbnails/52.jpg)
Plasma Cytokine
52(Chen et al., 2012)