Ruolo della donazione specifica di metili in neurologia: depressione ed iperomocisteinemia

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1 RUOLO DEI NUTRACEUTICI NELLA PRATICA CLINICA: novità ed evidenze scientifiche Centro Congressi Unione Industriale Torino 28 marzo 2015 Ruolo della donazione specifica di metili in neurologia: depressione ed iperomocisteinemia Prof. Riccardo Torta Direttore SCDU Psicologia Clinica e Oncologica Città della Salute e della Scienza Università di Torino

2 Mood depression: prevalence 2

3 ipertensione diabetologia reumatologia 22,4 22,7 25,3 oncologia pneumologia cardiologia neurologia 30,3 30,9 34,6 37,

4 Reazione psicologica a disabilità, perdita di ruolo, dolore cronico.. Malattie Somatiche Depressione Iatrogena: steroidi, interferone, citochine, antiestrogeni Patologie del SNC: stroke, demenze, tumori, Parkinson, SM, etc.

5 Mood depression: pathogenesis 5

6 dysphoric mood irritability loss of interest lost of pleasure AFFECTIVE psychomotor changes impaired concentration decision-making BEHAVIOURAL DEPRESSIVE CLUSTERS COGNITIVE coping styles alterations in appetite weight sleep patterns sexual desire SOMATIC increased fatigue headaches other chronic pains impaired memory cognitive distortion

7 reduced brain monoaminergic transmission oxidative stress and nitric oxide neurotrasnmitter receptor dysfunction Major depression reduction of neurotrophic factors dysregulation HPA HPG HPT axis increase of proinflammatory cytokines

8 Mood depression: screening 8

9 Mood Depression and Stress : in oncology clinics we need fast, easy and accurate screening tools depression anxiety stress HADS-D HADS-A DT+ PL self-evaluating instruments given to patients in waiting rooms followed by a structured interview if score > cutoff

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12 DT scores correlate with hypothalamic and midbrain areas Physical Problems (basal ganglia, amygdala, pons - LC) The HADS-Depression scores showed the most extended pattern (HPA, frontal cortex, ACC) positive correlation between DT scores and the activity of stress-related brain areas the higher the DT score, the higher the brain metabolism in involved brain areas

13 Mood depression: treatment strategies 13

14 Mood Treatment Options Traditional antidepressants high efficacy side effects adherence breastfeeding interactions omega 3 fatty acid folate S-Adenosyl-Methionine (SAMe) hypericum Complementary and alternative medicine Psychological interventions individual psychotherapies group psychotherapies psychoeducational interventions counselling

15 Reboxetine Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram Escitalopram SSRIs NARIs substituded benzamides Amisulpride ADs melatonergic Amitriptyline Clomipramine TCAs Venlafaxine Duloxetine SNRIs NDRIs Bupropione Agomelatine 15

16 Profilo farmacodinamico dei farmaci antidepressivi -1 H1 TCA M1 SSRI SRI SNRI SRI NRI SRI -2 NARI 1 SARI SRI 5HT3 NaSSA H1 5HT2a 5HT2A 5HT2C

17 Adverse Effects Linked with Pharmacological Profile Blurred vision Dry mouth Constipation Sinus tachycardia Urinary retention Memory dysfunction Sedation/ drowsiness Weight gain Ach antagonism H1 antagonism α 1 antagonism Psychomotor activation Psychosis DA reuptake inhibition Traditional Antidepressants α 2 antagonism Sexual dysfunction Activating side effects 5HT 2 agonism NE reuptake inhibition 5-HT reuptake inhibition Nausea GI disturbances Activating effects Dizziness Reflex tachycardia

18 Dinamica temporale degli effetti degli antidepressivi 8 6 Settimane di trattamento con antidepressivi Effetti sinaptici ore - giorni Effetti collaterali ore - giorni Effetti terapeutici 4-6 settimane

19 efficacy side effects symptoms improvement tolerability Drug safety outcome balance pt s satisfaction interactions impact on somatic disease

20 reduced brain monoaminergic transmission oxidative stress and nitric oxide neurotrasnmitter receptor dysfunction Major depression reduction of neurotrophic factors dysregulation HPA HPG HPT axis increase of proinflammatory cytokines hystone methylation hypothesis

21 There are serious limitations to the current monoamine theory. Additional mechanisms, including HPA axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. reduced brain monoaminergic transmission new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways related to depression dysregulation HPA HPG HPT axis Chromatin regulation, clock genes expression are involved in mood disorders, HPA axis regulation and GR system hystone methylation hypothesis

22 Histones methylation and mood depression 22

23 Modified by Nature Neuroscience, 2004 High-licking behaviour Sensibility to stress Ridotto leccamento, inadeguato allattamento sono associati con una alterata metilazione a livello dei geni preposti alla codificazione del recettore per i glucorticoidi e tale modifica determina un aumentata risposta allo stress nell adulto Mother Low-licking behaviour Low High

24 The DNA methylation state of specific genes in the 5-HT system (serotonin transporter) and HPA axis (GRs and AV) that is associated with early life experience may potentially lead to depression vulnerability

25 Genetic association studies and animal models implicate multiple lysine methyltransferases (KMTs) and demethylases (KDMs) in the neurobiology of emotion and cognition.

26 Methyl donors and mood depression 26

27 Inhibitory activity of S-adenosil-L-methionine on serum gamma-glutamyl-transpeptidase increase induced by psychodrugs and anticonvulsants Current Therapeutic Research 44, , 1988 Torta R e al. U/l 250 SAMe enhancement of the thymoleptic activity of TCAs with a shortened latency of the onset of antidepressant action Tranylcipromine Isocarboxazide Phenelzine T0 T90 T180 Current Therapeutic Research 55, 7, Torta R e al. 300 Dep. T0 Dep. T5 Controls S-adenosyl-l-methionine Normalizes P300 Latency In Patients With Major Depression

28 1 = methionine adenosyl transferase 2 = x-methyltransferase 3 = S-adenosylhomocysteine hydrolase 4 = methionine synthetase 5 = betaine homocysteine methyltransf. 6 = dihydrofolate reductase 7 = serine hydroxymethyltransferase 8 = 5,10-methylene-tetrahydrofolate red. 9 = dihydrobiopterin reductase 10 = tyrosine or tryptophan hydroxylase methyl donor X-CH 3 SAH 2 SAMe 3 Betaine Dimethyl glycine 1 Homocysteine 5 4 Methionine

29 S-adenosylmethionine (SAM) is the major methyl donor in the cell Methyl groups dietary sources; methionine, betaine, choline, 5 methyltetrahydrofolate

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31 5-MTHF as methyl donor CH3 Folate deficiency cause mood depression

32 1 = methionine adenosyl transferase 2 = x-methyltransferase 3 = S-adenosylhomocysteine hydrolase 4 = methionine synthetase 5 = betaine homocysteine methyltransf. 6 = dihydrofolate reductase 7 = serine hydroxymethyltransferase 8 = 5,10-methylene-tetrahydrofolate red. 9 = dihydrobiopterin reductase 10 = tyrosine or tryptophan hydroxylase SAH 3 Homocysteine X-CH 3 2 Betaine 5 Dimethyl glycine SAMe 1 Methionine 4 5-HTP L-DOPA 7,8-BH2 qbh2 5-CH 3 -H 4 folate H 4 folate Tryptophan Tyrosine BH4 5,10-CH 2 -H 4 folate H 2 folate

33 X-CH 3 SAH 2 SAMe methyl donor homocysteine cycle 3 Homocysteine Betaine 5 Dimethyl glycine 1 Methionine 4 5-HTP L-DOPA 7,8-BH2 qbh2 5-CH 3 -H 4 folate H 4 folate folate cycle Tryptophan Tyrosine BH4 5,10-CH 2 -H 4 folate H 2 folate

34 Hyperhomocysteinemia and mood depression 34

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36 deficit MS deficit MTHFR deficit CBS Malfunzionamento dei meccanismi riparativi del DNA metilato-correlati Inibizione dell azione vasodilatativa del NO: aggravamento stress ossidativo (Sainani 2002) thcy come fattore di rischio per sviluppo di DWMHs e PWMHs (Huang et al. 2010) 10-30% di sora thcy in PK pts trattati con L-DOPA (Belcastro et al., 2010) Meccanismi trombotici multipli Fattore endoteliale V inibizione proyteina C Ridotta attività antitrombina III Aumento adesione endoteliale Aumento adesione e aggregazione PLT

37 METABOLISMO OMOCISTEINA Via della metilazione Acido folico betaina Via della transulfurazione

38 X-CH 3 SAH 2 SAMe methyl donor homocysteine cycle 3 Homocysteine Betaine 5 Dimethyl glycine 1 Methionine 4 5-HTP L-DOPA 7,8-BH2 qbh2 5-CH 3 -H 4 folate H 4 folate folate cycle Tryptophan Tyrosine BH4 5,10-CH 2 -H 4 folate H 2 folate

39 Choline-sparing effect of betaine Choline more available for lipid metabolism homocysteine reduction SAMe increase Betaine as methyl donor Methionine-sparing effect of betaine Methionine more available for protein synthesis

40 betaine a methyl donor participating exclusively in the homocysteine cycle causes both homocysteine reduction and increased blood SAMe level.

41 SAMe 400 mg x 2/day vs SAMe 250 mg + betaine 125 mg x 3/day

42 Take home messages coinvolgimento dei meccanismi metilativi nella patogenesi della depressione possibilità di intervento con sostanze metilanti naturali, efficaci e ben tollerate efficacia antidepressiva e sicurezza della SAMe potenziamento da betaina e protezione da un incremento di omocisteina azione positiva su umore, cognitività e fatigue

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