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LE Magazine April 1997

Oxidative damage caused by free radicals produced during catecholamine autoxidation:
Protective effects of O-methylation and melatonin

Miller J.W.; Selhub J.; Joseph J.A.
Department of Pharmacology,
Duke University Medical Center, Box 3813, Durham, NC 27710 USA
Free Radical Biology and Medicine (USA) , 1996, 21/2 (241-249)

Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of Melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum beta-phycoerythrin (beta-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O- methyldopa significantly decreased the rate of beta-PE oxidation. When Melatonin was added to the ORAC assay in combination with dopamine or L- dopa, the rate of beta-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and Melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.

Protective effect of Melatonin against hippocampal DNA damage induced by intraperitonealadministration of kainate to rats

Uz T; Giusti P; Franceschini D; Kharlamov A; Manev H
Neurosciences Research Center, Allegheny-Singer Research Institute, Pittsburgh, PA 15212, USA
Neuroscience (UNITED STATES) Aug 1996, 73 (3) p631-6,

The pineal hormone Melatonin protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors and from oxidative stress-induced DNA damage and apoptosis. Intraperitoneal injection on kainate into experimental animals triggers DNA damage in several brain areas, including the hippocampus. It is not clear whether Melatonin is neuroprotective in vivo. In this study, we tested the in vivo efficacy of Melatonin in preventing kainate-induced DNA damage in the hippocampus of adult male Wistar rats. Melatonin and kainate were injected i.p. Rats were killed six to 72 h later and their hippocampi were examined for evidence of DNA damage (in situ dUTP-end-labeling, i.e. TUNEL staining) and for cell viability (Nissl staining). Quantitative assay was performed using computerized image analysis. At 48 and 72 h after kainate we found TUNEL-positive cells in the CA1 region of the hippocampus; in the adjacent sections that were Nissl-stained, we found evidence of cell loss. Both the number of TUNEL-positive cells and the loss of Nissl staining were reduced by i.p. administration of Melatonin (4 x 2.5 mg/kg; i.e. 20 min before kainate, immediately after, and 1 and 2 h after the kainate). Our results suggest that Melatonin might reduce the extent of cell damage associated with pathologies such as epilepsy that involve the activation of kainate-sensitive glutamate receptors.

Neuroprotection by Melatonin from kainate-induced excitotoxicity in rats

Giusti P; Lipartiti M; Franceschini D; Schiavo N; Floreani M; Manev H
Department of Pharmacology, University of Padua, Italy
FASEB J (UNITED STATES) Jun 1996, 10 (8) p891-6,

In this study, we injected 10 mg/kg kainate i.p. into rats. This resulted in a brain injury, which we quantified in the hippocampus, the amygdala, and the pyriform cortex. Neuronal damage was preceded by a set of typical behavioral signs and by biochemical changes (noradrenaline decrease and 5-hydroxyindoleacetic acid increase) in the affected brain areas. Melatonin (2.5 mg/kg) was injected i.p. four times: 20 min before kainate, immediately after, and 1 and 2 h after the kainate. The cumulative dose of 10 mg/kg Melatonin prevented kainate-induced neuronal death as well as behavioral and biochemical disturbances. A possible mechanism of melatonin-provided neuroprotection lies in its antioxidant action. Our results suggest that Melatonin holds potential for the treatment of pathologies such as epilepsy-associated brain damage, stroke, and brain trauma.

The hypothermic effect of Melatonin on core body temperature: Is more better?

Dawson D; Gibbon S; Singh P
Centre for Sleep Research, School of Psychology, University of South Australia, Queen Elizabeth Hospital, Australia
J Pineal Res (DENMARK) May 1996, 20 (4) p192-7,

Recent studies have shown that Melatonin is both hypnotic and hypothermic at physiological levels. Indeed, the hypnotic effect may be mediated via the hypothermic action. If this is the case, it is important to explore the dose-response relationships for the thermoregulatory effects of melatonin. Four groups of eight healthy adults (n = 32), aged between 18 and 38, each underwent two 12-hr bedrest protocols in which core body temperature (CT) and plasma Melatonin levels were measured concurrently between 0800 and 2000 hr. For each group, subjects ingested either sucrose placebo or a 0.1, 0.5, 1.0, or 5.0 mg Melatonin capsule at 1600 hr in a double-blind counterbalanced cross-over design. Melatonin was absorbed rapidly, with peak levels being reached after 1 hr at all dose levels. Mean peak plasma Melatonin levels increased from physiological to pharmacological levels in a dose-dependent manner. Elimination for all dose levels was rapid, with mean plasma half-lives between 33 and 47 min. At the lower doses the mean drop in CT was between 0.05 and 0.15 degrees C and took between 2 and 3 hr. At the higher doses (1.0 and 5.0 mg), CT fell by 0.25-0.3 degrees C within 30-60 min following ingestion and at the highest dose (5 mg) remained suppressed for the duration of the study. While the magnitude and duration of the drop increased in what appeared to be a dose-dependent manner, it is unlikely that this relationship reflects a simple dose-response curve. There was considerable variability in plasma profiles following administration, particularly at the two lowest doses (0.1 and 0.5 mg). The lower mean drop in CT probably reflects the lower proportion of subjects achieving physiological plasma levels, and therefore a hypothermic effect, at the two lowest doses. If Melatonin is to be used to improve sleep onset and maintenance by lowering CT, doses between 1.0 and 5.0 mg appear to be the lowest that produce a consistent drop in CT across all subjects.

The zinc pool is involved in the immune-reconstituting effect of Melatonin in pinealectomized mice

Mocchegiani E; Bulian D; Santarelli L; Tibaldi A; Muzzioli M; Lesnikov V; Pierpaoli W; Fabris N
Gerontol. Res. Dept., Italian National Research Centres on Aging, Ancona, Italy
J Pharmacol Exp Ther (U.S.) Jun 1996, 277 (3) p1200-8,

Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.

Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells

Shultz TD; Chew BP; Seaman WR; Luedecke LO
Department of Food Science and Human Nutrition,
Washington State University, Pullman 99164-6376
Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33,

The effects of physiologic concentrations of conjugated linoleic acid (CLA) and beta-carotene were assessed on human (M21-HPB, malignant melanoma; HT-29, colorectal; MCF-7, breast) cancer cells. The incubation of cancer cells with CLA showed significant reductions in proliferation (18-100%) compared to control cultures. M21-HPB and MCF-7 cell mortality was dose- and time-dependent. beta-Carotene was inhibitory to breast cells only. MCF-7 cells supplemented with CLA incorporated significantly less [3H]leucine (45%), [3H]uridine (63%) and [3H]thymidine (46%) than control cultures. M21-HPB and HT-29 cells supplemented with CLA incorporated less [3H]leucine (25-30%). These in vitro results suggest that CLA and beta-carotene may be cytotoxic to human cancer cells in vivo.

Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat

Ip C; Singh M; Thompson HJ; Scimeca JA Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263 Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5,

Conjugated linoleic acid (CLA) is a collective term which refers to a mixture of positional and geometric isomers of linoleic acid. It is naturally occurring in meat and dairy products. We have previously reported (Ip, C., Chin, S. F., Scimeca, J. A., and Pariza, M. W. Cancer Res., 51: 6118-6124, 1991) that 1% CLA in the diet suppressed mammary carcinogenesis in rats given a high dose (10 mg) of 7,12-dimethylbenz(a)anthracene. In the present study, dietary CLA between 0.05 and 0.5% was found to produce a dose-dependent inhibition in mammary tumor yield when fed chronically to rats treated with a lower dose (5 mg) of 7,12-dimethylbenz(a)anthracene. Short-term CLA feeding for 5 weeks, from weaning to the time of carcinogen administration at 50 days of age, also offered significant protection against subsequent tumor occurrence. This period corresponds to maturation of the mammary gland to the adult stage in the rat. The inhibitory response to short-term CLA exposure was observed with the use of 2 different carcinogens: 7,12-dimethylbenz(a)anthracene and methylnitrosourea. The fact that CLA was protective in the methylnitrosourea model suggests that it may have a direct modulating effect on susceptibility of the target organ to neoplastic transformation. The proliferative activity of the mammary epithelium was assessed by the incorporation of bromodeoxyuridine. Immunohistochemical staining results showed that CLA reduced the labeling index of the lobuloalveolar compartment, but not that of the ductal compartment of the mammary tree. Since the lobuloalveolar structures are derived from the terminal end buds which are the sites of carcinogenic transformation, the above finding is consistent with the bioassay data of tumor inhibition. Thus, changes in gland development and morphogenesis may be a locus of action of CLA in modulating mammary carcinogenesis. CLA is a unique anticarcinogen because it is present in foods from animal sources. Furthermore, its efficacy in cancer protection is manifest at dietary concentrations which are close to the levels consumed by humans.

Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionin

Bottiglieri T; Godfrey P; Flynn T; Carney MW; Toone BK; Reynolds EH Department of Neurology, King's College Hospital, London, U.K.
J Neurol Neurosurg Psychiatry (ENG.) Dec 1990, 53 (12) p1096-8,

Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.

The antidepressant potential of oral S-adenosyl-l-methionine

Rosenbaum JF; Fava M; Falk WE; Pollack MH; Cohen LS; Cohen BM; Zubenko GS
Clinical Psychopharm. Unit, Mass. General Hospital, Boston 02114
Acta Psychiatr Scand (DENMARK) May 1990, 81 (5) p432-6,

S-adenosyl-l-methionine (SAMe), a naturally occurring brain metabolite, has previously been found to be effective and tolerated well in parenteral form as a treatment of major depression. To explore the antidepressant potential of oral SAMe, we conducted an open trial in 20 outpatients with major depression, including those with (n = 9) and without (n = 11) prior history of antidepressant nonresponse. The group as a whole significantly improved with oral SAMe: 7 of 11 non-treatment-resistant and 2 of 9 treatment-resistant patients experienced full antidepressant response. Side effects were mild and transient.

Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial

Kagan BL; Sultzer DL; Rosenlicht N; Gerner RH
Department of Psychiatry, West Los Angeles VA Medical Center, CA.
Am J Psychiatry (UNITED STATES) May 1990, 147 (5) p591-5,

Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

S-adenosylmethionine in the treatment of depression

Vahora SA; Malek-Ahmadi P
Texas Tech University, School of Medicine, Department of Psychiatry, Lubbock 79430
Neurosci Biobehav Rev (U.S.) Summer 1988, 12 (2) p139-41,

The antidepressant property of S-adenosylmethionine (SAMe) has been supported by several uncontrolled and controlled studies. Compared to standard antidepressant agents, SAMe has fewer side-effects and shorter lag period. Future studies to delineate SAMe-responsive depression are warranted. (38 Refs.)

S-adenosylmethionine treatment of depression: a controlled clinical trial

Bell KM; Plon L; Bunney WE Jr; Potkin SG
University of California, Irvine Medical Center, Orange 92668
Am J Psychiatry (UNITED STATES) Sep 1988, 145 (9) p1110-4,

The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14 days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study.

S-Adenosylmethionine Treatment of Depression in patients with Parkinson's Disease:
a double-blind crossover study versus placebo

Carrieri P.B.; Indaco A.; Gentile S.; Troisi E.; Campanella G. Clinica Neurologica, Il Facolta di Medicina e Chirurgia, Universita di Napoli, Napoli, Italy Curr Ther Res Jul 1990, 48 (1) p164,
Depression is frequently observed in patients with Parkinson's Disease (PD). A double-blind, crossover study versus placebo was conducted in 21 patients with PD and depression treated with S-adenosylmethionine (SAMe), an endogenous methyl donor. Duration of the study was 30 days for each arm, with a washout period of two weeks between treatments. At each evaluation, the Webster Rating Scale, the Northwestern University Disablility Scale, the Hamilton Rating Scale for Depression, and the Beck Self Depression Inventory were used. SAMe was administered at a dose of 400 mg. BID orally plus 200 mg IM daily. SAMe improved depression in patients with PD to a statistically larger extent than did placebo, although Parkinson symptoms appeared to be unchanged. Side effects were moderate and of a brief duration.

Oral S-adenosyl-L-methionine in depression

Vanna M. DE; Rigamonti R.
University Psychiatric Department, University of Trieste, Trieste, and Psychiatric Unit, Ospedale Civile, Gorizia, Italy
Curr Ther Res Sep 1992, 52 (3), p478,

The antidepressant activity of oral S-adenosyl-L-methionine (SAMe) was evaluated in a randomized, double-blind, imipramine-controlled trial in 30 patients with major depression. The results suggest that oral SAMe is a safe, effective antidepressant with negligible side effects and a rapid onset of action. Only one patient became hypomanic but did not drop out of the study. SAMe may be useful for patients who cannot tolerate other antidepressant agents of for patients with other risk factors. These findings suggest a role for methylation in the pathophysiology of depression.

Results of treatment with S-adenosyl-L-methionine in patients with major depression and internal illnesses

Criconia AM; Araquistain JM; Daffina N; Navajas F; Bordino M
Department of Internal Medicine, Ospedale Cristo Re, Rome, Italy
Curr Ther Res June 1994, 55 (6), p666,
Forty-eight patients with major depression associated with internal illnesses of various origins were enrolled for 4 weeks of treatment with S-adenosyl-L-methionine (SAMe). the medication was administered parenterally (400 mg daily either intravenously or intramuscularly) in inpatients and orally (800 mg daily) in outpatients. Evaluations were performed via Becks Depression Inventory (BDI) by comparing the scores on day 28 with baseline values. Statistically significant differences were observed (P 0.01). Although minor adverse side effects were reported, they were not severe enough to withdraw medication. SAMe treatment proved to be effective and relatively safe in depressed patients with associated internal illnesses.

Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous electrical nerve
stimulation in primary fibromyalgia

Benedetto P Di; Iona LG; Zidarich V
Rehabilitation Center, Ospedale Santoro, Trieste, Italy
Curr Ther Res Feb 1993, 53 (2), p222,

The effects of S-adenosyl-L-methionine (SAMe) and transcutaneous electrical nerve stimulation (TENS) were evaluated in a 6-week controlled trial of 30 patients with primary fibromyalgia. Unlike TENS, SAMe significantly decreased the total number of tender points, had a significant beneficial effect on the subjective symptoms of pain and fatigue, and significantly reduced the scores on the Hamilton Depression and Anxiety Rating Scales and Zung's Self-Rating Scale for Depression. At the end of treatment, patients in the TENS group exhibited significantly reduced scores on the Hamilton Anxiety Scale only.

St John's wort for depression-an overview and meta-analysis of randomised clinical trials

Linde K; Ramirez G; Mulrow CD; Pauls A; Weidenhammer W; Melchart D
Projekt Munchener Modell, Ludwig-Maximilians-Universitat, Munich, Germany
BMJ (ENGLAND) Aug 3 1996, 313 (7052) p253-8,

OBJECTIVE-To investigate if extracts of Hypericum perforatum (St John's wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. DESIGN-Systematic review and meta-analysis of trials revealed by searches. TRIALS-23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. MAIN OUTCOME MEASURES-A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. RESULTS-Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. CONCLUSION-There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.

Treatment of depressive symptoms with a high concentration hypericum preparation-a multicenter placebo-controlled double-blind study

Witte B; Harrer G; Kaptan T; Podzuweit H; Schmidt U
Arbeits- und Forschungsgemeinschaft fur Arzneimittel-Sicherheite. V., Koln
Fortschr Med (GERMANY) Oct 10 1995, 113 (28) p404-8,

In a multicenter, placebo-controlled double-blind trial, the effect on depression (ICD 10 F 32.1) of treatment with an innovative highly concentrated hypericum preparation was investigated. The study contained 97 outpatients who received 100 to 120 mg of the hypericum extract bid. The course of the illness was assessed with the Hamilton Depression Scale (HAMD), the von Zerssen Depressivity Scale (D-S) and the Clinical Global Impression Scale (CGIS). Treatment resulted in an appreciable improvement in the symptoms of depression, and the 70% response rate (n = 43), corresponded to that of chemical antidepressants. The preparation also showed an anxiolytic effect. The substance was extremely well tolerated, and no side-effects were reported by any of the patients.

Hypericum in the treatment of seasonal affective disorders

Martinez B; Kasper S; Ruhrmann S; Moller HJ
Psychiatrische Universitatsklinik Bonn, Germany
J Geriatr Psychiatry Neurol (U.S.) Oct 1994, 7 Suppl 1 pS29-33,

Seasonal affective disorder (SAD) represents a subgroup of major depression with a regular occurrence of symptoms in autumn/winter and full remission in spring/summer. Light therapy (LT) has become the standard treatment of this type of depression. Apart from this, pharmacotherapy with antidepressants also seems to provide an improvement of SAD symptoms. The aim of this controlled, single-blind study was to evaluate if hypericum, a plant extract, could be beneficial in treating SAD patients and whether the combination with LT would be additionally advantageous. Patients who fulfilled DSM-III-R criteria for major depression with seasonal pattern were randomized in a 4-week treatment study with 900 mg of hypericum per day combined with either bright (3000 lux, n = 10) or dim ( 300 lux, n = 10) light condition. Light therapy was applied for 2 hours daily. We found a significant (MANOVA, P .001) reduction of the Hamilton Depression Scale score in both groups but no significant difference between the two groups. Our data suggest that pharmacologic treatment with hypericum may be an efficient therapy in patients with seasonal affective disorder.

Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160

Hansgen KD; Vesper J; Ploch M
Institut fur Psychologie, Universitat Fribourg/Schweiz, Germany
J Geriatr Psychiatry Neurol (U.S.) Oct 1994, 7 Suppl 1 pS15-8,

Seventy-two depressive patients of 11 physicians' practices were treated in a double-blind study for a period of 6 weeks either with hypericum extract LI 160 or with placebo. Inclusion criterion was a major depression in accordance with DSM-III-R. The changes were assessed using four psychometric scales (HAMD, D-S, BEB, CGI). After 4 weeks of therapy, the statistical evaluation revealed a significant improvement in all four psychometric tests in the active group as compared to the placebo group. After switching the placebo group to active treatment (5th to 6th week of therapy), significant improvements were found in the original placebo group. No serious side effects were observed.