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Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence.

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Presentation on theme: "Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence."— Presentation transcript:

1 Ru-Band Lu, MD. Shiou-Lan Chen, PhD. National Cheng Kung University Neuro-degeneration and Novel Treatment in Heroin dependence

2 Neurodegeneration in Mental Illnesses Schizophrenia Bipolar disorders Substance use disorders (alcohol) Anxiety disorders? Personality disorders? 2

3 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

4 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

5 MRI in middle-aged women Neuronal degeneration in Substance Abuse 5

6 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

7 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

8 Microglia Source for neurotrophin production Target for anti-inflammation Astroglia Glial cells : Key roles in disease and prime targets for therapy 8

9 9 Hypothesis 1.Neuronal Degeneration 2.White/Gray Matter Damage Causing/Onset /Relapse of Mental Illness The activation of Neuro-immune system Brain Blood Blood-Brain-Barrier Cytokines

10 Qin et al. (2007) h1h2h3h6h9h7 m10 m TNF  (% of peak) Time A single IP LPS injection induced TNF-α production both in peripheral and brain in rat Liver ** Brain ** Blood ** TNF-  LPS Kupffer cell

11 Role of microglia in toxin-induced progressive neurotoxicity Pro-inflammatory Factors (ROS, NO., TNFa, IL-1, PGs) Reactive Microgliosis (Self-propelling) LPS (Extra Neurotoxin) Activation MPTP (Intra Neurotoxin) Microglia (Working Model) Dopaminergic Neuronal Damage 11 (Hong et al., 2005)

12 NADPH oxidase (PHOX) Activated O2O2 O2 –O2 – NADPH NADP + + H + Resting gp91 p22 rap1a p40 p47 rac2 p67  MAC-1 LPS out in PKC P P Naloxone, Dextromethorphan Memantine 12 (Hong et al., 2005)

13 Transfection of gp91 PHOX, a membrane subunit of PHOX, increases [ 3 H]-naloxone binding [ 3 H]-(-)-Nal Binding Capacity (% WT) WT [ 3 H]-(+)-Nal * Gp91- transfected 400 COS-7 Cells (WT) Ligand Binding Assay Stable Transfection COS-7 gp91 ( gp91 ) gp91 * 13 (Hong et al., 2007)

14 O2O2 O 2 – Dual Functions of Superoxide Radicals gp91 Microglia MAC1 TLR4 LBP CD14 PHOX ROS H2O2H2O2 O 2 – TNF-  IL-1 NO ONOO - 2) Gene Expression 1) Neurotoxicity NF-kB,AP-1 PKC LPS DA neurons 14 (Hong et al., 2005)

15 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)

16 LPS Microglia TNF-a IL-1b Neuronal death ONOO - NO O 2 - 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)

17 Memantine LPS Dopaminergic Neuron ONOO - TNFα IL-1β NOO 2 - Microglia PHOX Inhibition of microglial PHOX (by binding to gp 91) is associated with DM-, Memantine-elicited neuroprotective effect 17 (wu et al., 2009)

18 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)

19 LPS Activation Trophic factors: (GDNF, BDNF, NGF) Pro-inflammatory factors: Superoxide, iROS NO, TNF , PGE 2 Reactive Microgliosis Astroglia Microglia DA neuron Inhibition Memantine Stimulation Memantine Combined therapy for neurodegenerative diseases (Self-propelling) Neurogenesis 19 (wu et al., 2009)

20 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

21 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

22 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

23 23 Human- Heroin dependence treatment

24 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)

25 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 levels 25 (Chen et al., submitted, 2013)

26 Correlation of heroin used period with plasma MTD dose, cytokines and BDNFat baseline Heroin used years vs MTD doseIL-8TGF-β1BDNF Spearman r % confidence interval to to to to P value (two-tailed) MTD, methadone; transforming growth factor (TGF)-β1; A non-parametric analysis (Chen et al., 2013)

27 Plasma cytokine, and brain-derived neurotrophic factor baseline data Heroin-dependent Patientsp-value Healthy Controls MTD+PlaceboMTD+Mem n = 72n = 57n = 58 Gender (F/M)10/6210/4710/ Age (years)31.64 ± ± 0.93 *** ± 0.94 *** < Heroin use (years)-7.49 ± ± MTD dose (mg) ± ± Plasam TNF-  (pg/mL)1.57 ± ± 0.47 *** 3.62 ± 0.34 *** < Plasma CRP (ng/mL)1.66 ± ± 0.44 *** 3.60 ± 0.38 *** < Plasma IL1-  (pg/mL)0.54 ± ± 0.28 ** 1.97 ± 0.27 *** < Plasma IL-6 (pg/mL)1.23 ± ± 0.35 ** 2.42 ± 0.28 ** Plasma IL-8 (pg/mL)1.38 ± ± 0.56 ** 6.53 ± 1.24 *** < Plasma TGF-  1 (ng/mL)32.27± ± 2.22 ** ± 2.00 ** Plasma BDNF (ng/mL) ± ± 1.18 *** 9.55 ± 0.83 *** < Mem, 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)

28 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)

29 Heroin dependence treatment Methadone + Memantine (5 mg/placebo) 29 (Chen et al., 2012)

30 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)

31 Heroin dependence treatment Methadone + Memantine (5 mg/placebo) 31 (Chen et al., 2012)

32 Heroin dependence treatment Methadone + Memantine (5 mg/placebo) 32 (Chen et al., 2012)

33 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

34 Comments Low dose Memantine – 5 mg/day of MM plasma level ng/ml (  M) – No effect in NMDA receptor antagonist (IC 50 : 2-3  M) ( Parsons et al. 1999) – Effective in heroin dependence treatment – Benefit in neuron protect & decreasing neurodegeneration 34

35 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

36 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

37 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

38 Thank you 38

39 39

40 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

41 Human peripheral effect 41

42 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 * * * DM (mg/kg) Lesion area (%) Control DM(10mg/kg) DM(20 mg/kg)DM(40 mg/kg) (Liu et al. 2009) 42

43 Placebo DM * † ‡ 0 36 Time (months) after DM (60 mg/tablet, bid) Flow mediated dilatation ratio Clinical trial of dextromethorphan (DM) in heavy smokers CRP levels (mg/dl ) Time (months) after DM (60 mg/tablet, bid) * * Placebo DM * * Blood flow-mediated dilatation ratioC-reactive protein (CRP) (Liu et al.) 43

44 Clinical trial of naltrexone in alcoholics 44 (Chen et al., 2012)

45 Neurotrophic and neuroprotective effects of memantine H.M. WU, H.L. CHEN, N.S. TZENG J.S. HONG, R.B. LU* (2009) 45

46 Memantine has neurotrophic and neuroprotective effects to dopaminergic neurons and against LPS-induced neurotoxicity 46 (Wu et al., 2009)

47 The neurotrophic effect of memantine is astrocyte-dependent. 47 (Wu et al., 2009)

48 Memantine decreases the levels of pro-inflammatory factors induced by LPS. 48 (Wu et al., 2009)

49 Memantine has independent neuroprotective effects on LPS-induced neurotoxcity. 49 (Wu et al., 2009)

50 Memantine attenuates LPS-induced morphological activation of microglia. 50 (Wu et al., 2009)

51 In Summary Pro-inflammatory Factors Reactive Microgliosis (Self-propelling) Microglia Neurons Trophic factors: (GDNF, BDNF, NGF) Neurogenesis Astroglia (1) (2) (-) Anti- inflammation Neuro- protection Neuronal genesis (+) 51

52 Plasma Cytokine 52 (Chen et al., 2012)


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