Natural polyphenolic coffee extract administration relieves chronic nociplastic pain in a reserpine-induced fibromyalgia-like female mouse model.

INTRODUCTION: Nociplastic pain involves reflexive and nonreflexive pain responses and it is a core symptom of fibromyalgia (FM). The increasing prevalence of this health condition and the low rates of patients' quality of life, combined with the lack of suitable pharmacologic treatments, evidence the demand to research new alternatives. Polyphenols may be potential therapeutic candidates as they have been reported to exert pathological pain modulation in preclinical models. In that context, this work was aimed to study the antinociceptive effects of a polyphenolic extract obtained from decaffeinated ground roasted coffee, in the RIM6 FM-like mouse model. METHODS: To this end, RIM6 adult ICR-CD1 female mice were administered daily once a week with either 10 or 15 mg/kg of extract, and reflexive pain responses were evaluated for up to 3 weeks. At the end, the depressive-like behavior was assessed as a nonreflexive pain response, and spinal cord and serum samples were collected for immunohistochemical and toxicological analyses. RESULTS: These findings showed that the repeated administration of the coffee polyphenolic extract (CE) modulated reflexive pain responses, depressive-like behavior, and spinal cord gliosis in a dose-dependent manner, without signs of systemic toxicity. CONCLUSION: Thus, the CE may be a potential pharmacological treatment suitable to relieve nociplastic pain responses characteristic of FM.

Involvement of peripheral mast cells in a fibromyalgia model in mice.

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.

Spinal dopaminergic D1 and D5 receptors contribute to reserpine-induced fibromyalgia-like pain in rats.

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D1-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D1 and D5 receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D1-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D1-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D1-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D1 and D5 receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D5 receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D1/D5 receptors in reserpine-induced hypersensitivity in rats.

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models.

Sigma-1 receptor (σ1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a σ1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of σ1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.

Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.

Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.

Nociceptive chemical hypersensitivity in the spinal cord of a rat reserpine-induced fibromyalgia model.

The pathological mechanisms of fibromyalgia (FM) are largely unknown. Recently, a rat reserpine-induced pain model showing exaggerated pain-related behaviors to mechanical and thermal stimuli has been used in FM research. However, the model has not been fully characterized. Here, we investigated nociceptive hypersensitivity to chemical stimuli and its spinal mechanisms to further characterize the model. The rat model was induced by administering reserpine to the nervous system. Nociceptive behaviors to chemical stimuli were quantified using the formalin pain test, and neuronal activation of the stimuli was examined using spinal c-Fos immunohistochemistry and electrophysiological recordings of superficial dorsal horn (SDH) neurons. The duration of pain-related behaviors was prolonged in both phases I (0-5 min) and II (10-60 min) and the interphase; and the number of c-Fos-immunoreactive nuclei increased in laminae I-II, III-IV, and V-VI at the spinal segments L3-L5 on the side ipsilateral to the formalin injection, and these factors were significantly and positively correlated. The action potentials of SDH neurons induced by formalin injection were markedly increased in rats treated with reserpine. These results demonstrate that pain-related behaviors are facilitated by noxious chemical stimuli in a rat reserpine-induced FM model, and that the behavioral hypersensitivity is associated with hyperactivation of SDH neurons.

Antiparkinsonian activity of Tabebuia impetiginosa bark and biochemical analysis of dopamine in rat brain homogenates.

OBJECTIVES: Improving economy and well-being in developing nations like India has expanded life expectancy and changed the attention from transmittable to non transmittable diseases such as Parkinson's disease. Tabebuia impetiginosa has been utilized by cultivators as a general tonic, immunostimulant, adaptogen and also in motor disorders. The present investigation was to explore the antiparkinsonian activity of Tabebuia impetiginosa bark by experimental methods. MATERIALS AND METHODS: Control group-I was served with distilled water. Group-II was considered as pathological control [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2mg/nostrils i.n, Reserpine 40mg/kg s.c, Haloperidol 0.5mg/kg, i.p]. Group-III served with standard drug (Apomorphine 40mg/kg, s.c). Group IV and V received aqueous extract of Tabebuia impetiginosa bark in doses of 300 and 500mg/kg/day respectively. Tremor, hypokinesia, muscular rigidity, catatonia, postural immobility, postural instability and catalepsy were assessed for antiparkinsonian activity. RESULTS: The bark extract served group exhibited the increased levels of dopamine (5700±1.84ng/g) when compared to control groups (4300±3.17ng/g). The extract at both the doses displayed a significant reduction in postural flexion, moderate decrease in tremor, muscular rigidity and postural immobility scores but do not exhibit significant lowering of hypokinesia score in reserpine induced Parkinsonian model. The reduction in catatonia and catalepsy scores is more remarkable in case of high dose of extract (500mg/kg) compared to standard drug in Neuroleptic induced Parkinsonism. CONCLUSION: The findings demonstrate that Tabebuia impetiginosa bark extract has significant anti-cataleptic potentials and the antioxidant effect of the bark may also be a significant contributor to its antiparkinsonian activity.

Therapeutic Approaches to Nociplastic Pain Based on Findings in the Reserpine-Induced Fibromyalgia-Like Animal Model.

Nociplastic pain, the third category of chronic pain, has emerged as a serious medical issue. Due to its significant negative influences on patients and society, high prevalence, and lack of sufficiently effective treatments, more efficacious therapies are required. This review highlights the potential therapeutic approaches identified in studies that used reserpine-induced myalgia (RIM) animal model that exhibits nociplastic pain-associated phenotypes. These studies have revealed that biologic processes including the chronic reduction of monoamines, increase of oxidative/nitrosative stresses and inflammatory mediators, upregulation of pronociceptive neurotransmitters and their receptors, increase of trophic factors, enhancement of the apoptotic pathway, sensory nerve sensitization, and activation of immune cells in central and/or peripheral regions underly the nociplastic pain-associated phenotypes in RIM animal model. Potential therapeutic approaches to nociplastic pain, i.e., 1) functional modification of specific molecules whose expression is distinctly altered following the chronic reduction of monoamines, 2) targeting the molecules that are responsible for other major categories of chronic pain (i.e., chronic inflammatory pain and neuropathic pain), 3) supplementation of nutrition to correct the disrupted nutritional balance, 4) improvement of physical constitution by natural substances, and 5) nonpharmacological interventions, have been identified. SIGNIFICANCE STATEMENT: Studies in reserpine-induced myalgia (RIM) animal model have revealed the pathologies that occur after the chronic reduction of monoamines and identified potential therapeutic approaches to nociplastic pain. Translation of their analgesic efficacy from RIM animal model to patients remains an issue to be addressed. Successful translation would lead to better therapies for nociplastic pain.

Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms. Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor ß (TGF-ß) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver. In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-ß expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.

Relevance of Mitochondrial Dysfunction in the Reserpine-Induced Experimental Fibromyalgia Model.

Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.

Spontaneous pain-associated facial expression and efficacy of clinically used drugs in the reserpine-induced rat model of fibromyalgia.

Fibromyalgia-associated chronic pain occurring without organic causes exerts negative effects on patients' quality of life, thereby necessitating the development of superior drugs. Since non-organic pain in patients with fibromyalgia occurs without external stimuli, an endpoint measure that reflects patients' spontaneous pain should be implemented in preclinical research. The present study is the first to apply the rat grimace scale (RGS), a facial expression-dependent measure developed for quantifying spontaneous pain, to the rat with reserpine-induced myalgia, an animal model of fibromyalgia exhibiting non-organic pain. Animals were videotaped and still images of facial expressions were captured and scored in a blind fashion. The reserpine-induced myalgia rats exhibited a significant increase in the RGS score, which was sustained for 2 weeks or more after the induction of fibromyalgia-like state by reserpine injection. The period of RGS score elevation was similar to that of reduced paw withdrawal threshold (PWT) measured using the von Frey filament test, a conventional measure of evoked pain. The elevated RGS score and the decreased PWT were relieved by gabapentin (an α2δ subunit ligand) and duloxetine (a serotonin and noradrenaline reuptake inhibitor), but not by diclofenac (a nonsteroidal anti-inflammatory drug), buprenorphine (a mu-opioid receptor agonist), or diazepam (a benzodiazepine). The present study suggests that facial expressions in reserpine-induced myalgia rats simulate non-organic pain occurring spontaneously in patients with fibromyalgia. This finding achieves a coordination of pain measures between the animal model and patients with fibromyalgia and would improve the translation of analgesic efficacies between them.

Monoamine system disruption induces functional somatic syndromes associated symptomatology in mice.

Functional somatic syndromes (FSS), a clinical condition manifesting a variety of unexplained somatic symptoms, has been proposed as an inclusive nosology encompassing individual syndromes such as fibromyalgia syndrome and irritable bowel syndrome. Accumulating evidence suggests that disturbance of the endogenous monoamine system could be involved in the aetiology of FSS. Therefore, the purpose of present study was to investigate whether the disturbance of the monoamine system would cause FSS-associated symptomatology in mice. The optimal dose of reserpine, an inducer of endogenous monoamines reduction, was first explored in mice. General body condition (body weight, rectal temperature, and ptosis) and FSS-associated symptomatology (paw withdrawal threshold, small intestinal transit, and locomotor activity) were measured. The concentration of monoamines was measured in central and peripheral tissues. Mice dosed with reserpine (0.25 mg/kg s.c., once daily for 3 consecutive days) exhibited a decrease in paw withdrawal threshold, delay in small intestinal transit, and reduction of locomotor activity without deterioration of general body condition on day 5 after the first reserpine injection. The concentration of monoamines was decreased in the central nervous system and skeletal muscle, but not in the small intestine. A reserpine dose of 0.5 mg/kg or more caused deterioration of general body condition. In conclusion, the optimal protocol of reserpine treatment for inducing pain symptom without deterioration of general physical condition is 0.25 mg/kg s.c., once daily for 3 consecutive days in mice. This protocol causes not only pain but also FSS-associated symptomatology which are associated with disruption of the endogenous monoamine system. The reserpine-treated animal may be useful for the research of not only fibromyalgia syndrome but also FSS, especially for the research focusing on the hypothesis that FSS is associated with the disturbance of endogenous monoamine system.

Curcumin Ameliorates Reserpine-Induced Gastrointestinal Mucosal Lesions Through Inhibiting IκB-α/NF-κB Pathway and Regulating Expression of Vasoactive Intestinal Peptide and Gastrin in Rats.

The objective of our study was to investigate whether curcumin protects against reserpine-induced gastrointestinal mucosal lesions (GMLs) in rats and to explore the mechanism of curcumin's action. Sprague-Dawley rats were randomly divided into four groups: control group, reserpine-treated group, reserpine treatment group with curcumin at high dose (200 mg/kg), and reserpine treatment group with curcumin at low dose (100 mg/kg). Rats in reserpine-treated group were induced by intraperitoneally administered reserpine (0.5 mg/kg) for 28 days. TUNEL staining and hematoxylin and eosin staining were used to evaluate the apoptotic cells and morphologic changes. In addition, to explore the mechanism of curcumin in protecting GMLs, we used serum of experimental rats to assess the level of vasoactive intestinal peptide (VIP), gastrin, interleukin-6, interleukin-10, tumor necrosis factor-α and interferon-γ by ELISA and radioimmunoassay. The protein levels of NF-κB, p-IκB-α, IκB-α, Bcl-2, Bax, and cleaved-caspase-3 were examined by western blot analysis. Data were analyzed with SPSS 19.0 software package. Curcumin treatment prevented tissue damage and cell death in the reserpine-treated rats and effectively decreased inflammatory response and balanced the expression of VIP and gastrin in the reserpine-treated rats. NF-κB, p-IκB-α, Bax, and cleaved-caspase-3 were increased in the reserpine group, but the curcumin high-dose group inhibited them. Curcumin can target the IκB-α/NF-κB pathway to inhibit inflammatory response and regulate the level of VIP and gastrin in reserpine-induced GML rats.

In vivo imaging of CREB phosphorylation in awake-mouse brain.

The cyclic adenosine monophosphate response element binding protein (CREB) is a phosphorylation-dependent transcription factor that plays important roles in memory consolidation and several neuropsychological disorders. Although analyzing the spatiotemporal pattern of CREB phosphorylation is required for elucidating the mechanism of memory consolidation, imaging of phosphorylation of a particular protein in the brain of live animals is impossible at present. Here, we developed a method for visualizing the CREB phosphorylation in the cerebral cortex of an awake mouse using a split luciferase technique. Using this technique, we demonstrated the correlation between the change in CREB phosphorylation at a particular region in the brain and behavioral consequences induced by the administration of reserpine, a psychotropic agent.

Korean ginseng extract attenuates reserpine-induced orofacial dyskinesia and improves cognitive dysfunction in rats.

Reserpine-induced orofacial dyskinesia in rats is an animal model of tardive dyskinesia that has been linked with free radical generation and oxidative stress. In the present study, reserpine (1 mg kg(-1), s.c.) was given to rats on days 1, 3 and 5 to induce orofacial dyskinesia, which is characterised by increased vacuous chewing and tongue protrusion. Sub-chronic treatment with Korean ginseng extract from day 1 to day 21 along with reserpine on days 1, 3 and 5 significantly and dose-dependently (100 and 200 mg kg(-1)) reduced reserpine-induced vacuous chewing movements and tongue protrusions. Reserpine-treated animals also showed poor retention of memory in the elevated plus maze paradigm. The sub-chronic Korean ginseng extract administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that repeated reserpine treatment significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of rats. Reserpine-treated rats also showed decreased levels of antioxidant defence enzymes, superoxide dismutase (SOD), and catalase. Sub-chronic administration of Korean ginseng extract dose-dependently and significantly reduced lipid peroxidation and restored decreased GSH levels by repeated reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The present study concludes that oxidative stress might play an important role in reserpine-induced abnormal oral movements, and Korean ginseng extract could be useful in the treatment of drug-induced dyskinesia and amnesia.

Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders.

BACKGROUND: Few drugs are available for the management of hyperkinetic movement disorders such as the dystonias, choreas, dyskinesias, and tics. Those that are available (primarily neuroleptics) are associated with a wide range of potentially serious adverse effects, including induction of tardive movement disorders. Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntington's disease. OBJECTIVE: This article reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, drug-interaction potential, and dosing and administration of TBZ. METHODS: MEDLINE was searched (1950-February 2010) for English-language articles investigating any aspect of TBZ. Search terms included tetrabenazine, Ro 1-9569, Nitoman, benzoquinolizines, and reserpine. The reference lists of the identified articles were searched for other pertinent publications, particularly those that were not indexed in the 1950s and 1960s. RESULTS: In the search for a chemical compound that was simpler than reserpine while preserving reserpine-like psychotropic activity, TBZ was identified in the 1950s as one member of a large group of benzoquinolizine derivatives. TBZ acts by depletion of the monoamines serotonin, norepinephrine, and dopamine in the central nervous system (CNS). It does this by reversibly inhibiting vesicle monoamine transporter type 2 and thus preventing monoamine uptake into presynaptic neurons. Clinical studies suggest that TBZ may have therapeutic applications in a wide range of hyperkinetic movement disorders. TBZ has been associated with numerous adverse effects, some of them serious and potentially fatal; these include parkinsonism, other extrapyramidal symptoms (particularly akathisia), depression and suicidality, neuroleptic malignant syndrome, and sedation. TBZ is subject to important drug-drug interactions with inhibitors and inducers of cytochrome P450 (CYP) 2D6, reserpine, and lithium. It is one of very few drugs whose dosing is based, in part, on the results of genotyping (in its case, genotyping for CYP2D6 metabolizer status). CONCLUSIONS: TBZ is a complicated drug in terms of its mechanism of action and its activities against the 3 major monoamines in the CNS, making it difficult to predict its efficacy and tolerability in patients with hyperkinetic movement disorders. It is associated with numerous adverse effects and several important drug-drug interactions. Much work remains to be done to determine the therapeutic potential of TBZ in the treatment of hyperkinetic movement disorders.

[Effect and mechanism of reserpine for changing salivary protein secretion in Pi-deficient rats].

OBJECTIVE: To study the effect of reserpine (RSP) for changing salivary protein secretion in Pi-deficient rats and to explore its possible mechanism. METHODS: Twenty rats allocated in the RSP group were given subcutaneous injection of RSP [0.4 mg/(kg x d)] for 9 successive days, while the other 20 rats in the control group were injected with same volume of saline instead. On the 10th day, ten rats randomly selected from each group were subjected for extracting saliva to detect salivary amylase activity (sAA) before and after an acid stimulation; and drawing blood from the orbital vein to measure the contents of vasoactive intestinal peptide (VIP) and cyclic adenosine monophosphate (cAMP). Then they were sacrificed and their parotids were taken out for pathological examination with HE staining, as well as for VIP and cAMP measuring, and zymogen granules counting under a transmission electron microscope. The remainder animals were stopped injecting and normally fed to 40 days, then subjected to be detected as above-mentioned. RESULTS: Food intake and body weight reduction were more significantly in the RSP group than in the control group. On the 10th day, the ratio of sAA before/after stimulation in the RSP group was 0.39 +/- 0.18, significantly lower than that in the control group (0.80 +/- 0.21, P < 0.01), but it was restored rapidly, reaching the normal range on the 25th day, on the 40th day, it became significantly different to the level on the 10th day (P < 0.05) and approached the level in the control group (P > 0.05). No significant pathological change of parotid was found in both groups; but the number of zymogen granules in the RSP group was remarkably more than that in the control group (41.4 +/- 4.9 vs 34.6 +/- 5.2, P < 0.01). Serum level of VIP in the RSP group was significantly less while that of cAMP was higher than that in the control group (22.5 +/- 13.1 mg/L vs 38.5 +/- 14.1 mg/L, and 125.8 +/- 15.5 micromol/L vs 105.3 +/- 16.7 micromol/L, both P < 0.05), but no inter-group difference was found in parotid tissue contents of both VIP and cAMP. All the indices detected became equivalent in the two groups on the 40th day. CONCLUSION: The reduction of salivary protein in Pi-deficient rats induced by RSP may be related to the regulatory pathway of VIP and cAMP.

[Identification of risk factors (the method of logistic regression)]. / Die Ermittlung von Risikofaktoren. Das Verfahren der logistischen Regression.

Logistic regression is a model used for prediction of an event (e.g. heart attack: yes/no) using several predictor variables whereas the output is confined to values between 0 and 1. The regression coefficients describe the size of the contribution of the risk factor. In this short introduction an example is used to explain the basic principle and the advantages of the logistic regression.

Protective effect of centrally-injected glucagon-like peptide-1 on reserpine-induced gastric mucosal lesions in rat: possible mechanisms.

BACKGROUND/AIMS: Intracerebroventricular glucagon-like peptide- 1 (GLP-1) has been shown to prevent the gastric mucosal lesions induced by reserpine. In the present study, we aimed to investigate the contribution of 1- the cholinergic pathway, 2- the sympathetic pathway, 3- somatostatin and 4- endogenous nitric oxide to this gastroprotective effect. METHODS: Rats were equipped with intravenous and intracerebroventricular cannulas under ether anesthesia for drug delivery. Rats were pretreated with mecamylamine (5 mg/kg; i.p.) and atropine sulfate (1 mg/kg; i.p.), yohimbine (1 mg/kg; i.p.), cysteamine (280 mg/kg; s.c.), and NG-nitro-L-arginine methyl ester (3 mg/kg; i.v.) to investigate the role of the cholinergic pathway, sympathetic pathway, somatostatin and endogenous nitric oxide, respectively, in the gastroprotective effect of GLP-1. To produce gastric mucosal lesions, reserpine was administered intraperitoneally at a dose of 25 mg/kg in 10 ml/kg of 0.5% acetic acid solution. Four hours later, the animals were decapitated, and their stomachs were removed and scored for mucosal damage. RESULTS: Glucagon- like peptide-1 (100 ng/10 microl; i.c.v.) inhibited the reserpine-induced gastric mucosal damage by 90% (p<0.01). Neither the nicotinic receptor antagonist mecamylamine (5 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine sulfate (1 mg/kg; i.p) affected the gastroprotective activity of GLP-1. On the other hand, pretreatment with yohimbine, an alpha2-adrenergic receptor antagonist (1 mg/kg; i.p.), cysteamine, a somatostatin depletor (280 mg/kg; s.c.), and NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (3 mg/kg; i.v.), significantly abolished the protective effect of GLP-1 on reserpine-induced gastric mucosal lesions (p<0.001, p<0.01 and p<0.01, respectively). CONCLUSIONS: We conclude that the sympathetic pathway, somatostatin and nitric oxide, but not the cholinergic pathway, contribute to the gastroprotective effect of intra-cerebroventricular GLP-1 on reserpine-induced gastric mucosal lesions.