International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

The impact of environmental enrichment on sex-specific neurochemical circuitries - effects on brain-derived neurotrophic factor and the serotonergic system.

Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild-types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/-) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner.

Depression-prone mice with reduced glucocorticoid receptor expression display an altered stress-dependent regulation of brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated protein.

Increasing evidence suggests that depression is characterised by impaired brain plasticity that might originate from the interaction between genetic and environmental risk factors. Hence, the aim of this study was to investigate changes in neuroplasticity following exposure to stress, an environmental condition highly relevant to psychiatric disorders, in glucocorticoid receptor-deficient mice (GR(+/-)), a genetic model of predisposition to depression. Specifically, we have analysed the neurotrophin brain-derived neurotrophic factor (BDNF) and the immediate-early gene activity-regulated cytoskeletal-associated protein (Arc), two closely related molecules that can contribute to neuroplastic and morphological changes observed in depression. We found a region-specific influence of the GR-genotype on BDNF levels both under basal and stress conditions. Steady-state levels of BDNF mRNA were unchanged in hippocampus while up-regulated in frontal lobe of GR(+/-) mice. Following exposure to an acute stress, increased processing from pro- to mature BDNF was observed in hippocampal synaptosomes of wild-type mice, but not in GR mutants. Furthermore, the stress-dependent modulation of Arc was impaired in the hippocampus of GR(+/-) mice. These results indicate that GR(+/-) mice show overt differences in the stress-induced modulation of neuroplastic proteins, which may contribute to pathologic conditions that may originate following gene x environment interaction.

Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain.

Accumulating evidence indicates that antidepressants alter intracellular signalling mechanisms resulting in long-term synaptic alterations which probably account for the delay in clinical action of these drugs. Therefore, we investigated the effects of chronic fluoxetine administration on extracellular signal-regulated kinase (ERK) 1 and 2, a group of MAPKs that mediate signal transduction from the cell surface downstream to the nucleus. Our data demonstrate that 3-week fluoxetine treatment resulted in long-lasting reduction of phospho-ERK 1 and 2. Such an effect depends on the length of the treatment given that no changes were observed after a single drug injection or after 2 weeks of treatment and it is region specific, being observed in hippocampus and frontal cortex but not in striatum. Finally, phospho-ERK 1 and 2 were differently modulated within nucleus and cytosol in hippocampus but similarly reduced in the same compartments of the frontal cortex, highlighting the specific subcellular compartmentalization of fluoxetine. Conversely, imipramine did not reduce the hippocampal phosphorylation of both ERK subtypes whereas it selectively increased ERK 1 phosphorylation in the cytosolic compartment of frontal cortex suggesting a drug-specific effect on this intracellular target. These results point to modulation of phosphorylation, rather than altered expression, as the main target in the action of fluoxetine on this pathway. The reduction of ERK 1/2 function herein reported may be associated with the therapeutic effects of fluoxetine in the treatment of depression.

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function.

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor.

A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.

A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor.

We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.

A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning.

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family. Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.

Modulation of fibroblast growth factor-2 by stress and corticosteroids: from developmental events to adult brain plasticity.

Neurotrophic factors are a heterogeneous group of peptides that play important roles on brain function at different development stages. Basic fibroblast growth factor (FGF-2), one of these molecules, is highly expressed in developing and adult brain. Its expression can be regulated under different experimental situations and this may be relevant for cellular vulnerability and brain plasticity. Stress and glucocorticoid hormones produce short- and long-term effects on brain function, which can involve the regulation of specific neurotrophic factors within selected brain structures. Treatments with corticosterone or dexamethasone up-regulate FGF-2 expression in different rat brain regions as well as in cultured astroglial cells. A similar elevation of FGF-2 biosynthesis is also observed in several brain regions following an acute restraint stress. This response is rapid and transient and, as FGF-2 is neuroprotective, may represent a defense mechanism through which the brain may limit the deleterious effect of stress over time. Moreover exposure to corticosterone during late stage of embryonic life (E18-E20) produces a significant reduction of FGF-2 mRNA levels in the adult hippocampus of male rats as well as changes in its acute modulation in response to stress or corticosterone. These data suggest that stress-related events taking place during brain maturation can modulate the expression of FGF-2 within selected brain regions thus contributing to permanent structural and functional alterations leading to an increased vulnerability to challenging life events.

Characteristics and financial performance of a pediatric faculty inpatient attending service: a resource-based relative value scale analysis.

OBJECTIVES: In many children's hospitals, inpatient attending physician services are provided by academic faculty who function as part-time inpatient specialists or hospitalists. Although some have claimed that hospitalist care can reduce length of stay and total hospital resource use and expenses, there are few benchmarks or data regarding physician productivity or the characteristics and financial performance of these programs. The resource-based relative value scale (RBRVS) is a valuable tool for developing national benchmarks and comparing the financial performance of inpatient programs at varying daily census and reimbursement levels. The objectives of this study were to 1) describe physician productivity on an inpatient service as measured by total relative value units (TRVUs) and professional charges, 2) determine whether inpatient collections were adequate to support faculty salaries for the time spent attending, and 3) develop a model to evaluate financial performance of inpatient programs at varying census and TRVU reimbursement levels. METHODS: A retrospective review of hospital discharge and faculty practice billing data between June 1997 and July 1998 was conducted in a general medical service in a regional, 208-bed, university-affiliated children's hospital in the Pacific Northwest. RESULTS: Of 4113 patients who were admitted to the children's hospital general medical service during a 12-month period, faculty part-time hospitalists (N = 28) served as the attending physician for 1738 (42%). On an annual basis, faculty attended for an average of 29.1 days (median: 21.0; range: 7.0-97.0), with an average daily patient census (ADC) of 7.2 (median: 6.5; range: 2.8-12.0). Inpatient attendings billed for 1738 initial visits and 3957 subsequent visits. Total physician productivity for the inpatient attending group during 1 year included 12 085 TRVUs and gross professional charges of $777 743. The average payment, or conversion factor (CF), was $24.46/TRVU (71% of Medicare CF). The cash collection rate was 38%, reflecting a payor mix that included 54% Medicaid, 28% commercial payors, 12% health maintenance organization, and 6% other payors. On a weekly basis, physicians generated an average of 109 TRVUs and collected $2665 in cash. The average salary cost per RVU was $23.40, and weekly faculty salary and benefit expenses were $2550. After operating expenses and academic taxes totaling 24% were deducted ($5.87/TRVU), RBRVS-based payments and cash collections covered 79% of average faculty weekly salaries. Financial modeling showed that either an average CF of $31/TRVU or an ADC of 9 patients per day on the inpatient service would be required to generate sufficient revenue to support physician salaries and operating expenses. CONCLUSIONS: For a faculty inpatient attending service in a children's hospital with an ADC of 7, a $24.46 RBRVS-based CF payment is inadequate to support faculty salaries and operating expenses for the time spent attending. Inpatient services in similar payor environments with comparable expenses and staffed by faculty who care for fewer than 9 patients per day will not cover typical faculty salary costs and operating expenses.

Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia.

The neonatal (PND 7) lesion of the ventral hippocampus (VH) with ibotenic acid represents a well-established experimental paradigm that recapitulates many schizophrenia-like phenomena. In order to investigate molecular changes that could contribute to long lasting consequences on brain function, we have investigated the effects of the VH lesion on the expression for the trophic factors FGF-2 and BDNF. We used RNase protection assay to measure their mRNA levels in cortical regions of prepubertal (PND 35) and young adult (PND 56) animals, both under basal condition as well as in response to an acute restraint stress. The expression of BDNF was not altered by the VH lesion in prefrontal (PFC) and frontal cortex (FC) of PND 35 or PND 56 rats. An acute restraint stress at PND 35 produced a significant increase of the neurotrophin expression in PFC of sham as well as lesioned animals. However in young adult animals a significant elevation of BDNF expression was observed only in sham rats. We also found that the VH lesion produced a significant reduction of basal BDNF mRNA levels in the cingulate cortex of young adult, but not prepubertal rats. This effect was not accompanied by changes in the acute modulation of the neurotrophin, which was up-regulated by stress in both experimental groups. Conversely the expression of FGF-2 at PND 35 and PND 56 was not altered by early postnatal VH lesion, and there were no major differences between sham and lesioned animals in response to the acute stress. The changes in trophic factor expression may be relevant for the long-term effects of VH lesion on synaptic plasticity and may determine an increased vulnerability of the brain under challenging situations.

Stimulatory role of dopamine on fibroblast growth factor-2 expression in rat striatum.

We have previously shown that systemic injection of (-)nicotine produces a selective up-regulation of fibroblast growth factor (FGF)-2 mRNA levels in rat striatum. Because (-)nicotine can increase striatal release of dopamine and glutamate, in the present study we have investigated the contribution of these neurotransmitters in the modulation of FGF-2 expression. We found that coinjection of dopaminergic D1 (SCH23390) or D2 (haloperidol) receptor antagonists prevents nicotine-induced elevation of FGF-2 expression. However, injection of the NMDA receptor antagonist MK-801 produced a significant increment of FGF-2 mRNA and protein levels in rat striatum similar to the effect produced by (-)nicotine alone. Interestingly this effect of MK-801 could also be prevented by D1 or D2 receptor antagonists, suggesting that an elevation of dopamine levels may be required for the regulation of the trophic molecule. Accordingly we found that the non-selective dopaminergic agonist apomorphine can similarly increase striatal FGF-2 mRNA levels. Despite the observation that both D1 and D2 receptors appear to contribute to the modulation of FGF-2 expression, only a direct activation of D2 receptors, through quinpirole administration, was able to mimic the effect of apomorphine. On the basis of FGF-2 neurotrophic activity, these results suggest that direct or indirect activation of dopaminergic system can be neuroprotective and might reduce cell vulnerability in degenerative disorders.

Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.

OBJECTIVE: To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro. METHODS: Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS). RESULTS: Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. CONCLUSION: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Calcium-dependent modulation of FGF-2 expression in cultured cerebellar granule neurons.

We investigated the expression for fibroblast growth factor-2 (FGF-2), in cultured rat cerebellar granule cells and its modulation by Ca2+ regulating agents. There were no significant differences in the levels of FGF-2 mRNA in cells cultured in high vs low K+. The expression of the trophic factor is induced by Ca2+ entry through the plasma membrane only in mature neurons but not at an early stage of maturation. Conversely the release of Ca2+ from intracellular stores increased the expression for FGF-2 at 2 or 7 days in culture. suggesting that is not dependent upon cellular maturation. These results suggest that specialized mechanisms can operate to regulate FGF-2 expression and that the integration of electrical and receptor-mediated signals for its modulation within cerebellar granule neurons may depend upon the maturational stage of the cells.

In vivo accuracy and reliability of color-coded image enhancements for the assessment of periradicular lesion dimensions.

OBJECTIVE: The purpose of this study was to compare dimensions on charge-coupled device-acquired images under various enhancements with dimensions on film radiographs and in vivo dimensions with respect to the linear measurement of periradicular radiolucent lesions. STUDY DESIGN: The dimensions of 25 lesions imaged by means of a charge-coupled device-based digital receptor and Ektaspeed Plus radiographic film were measured and compared with dimensions as actually measured on impressions of the lesions taken during surgery. Digital images were displayed in unenhanced, equalized, and equalized/color-coded modes. The color-coding protocol was repeated to determine the method error, and each image treatment was also remeasured to determine intrarater reliability. Differences were compared through use of a Friedman 2-way analysis of variance with a follow-up Wilcoxon signed rank test (alpha = 0.01). RESULTS: Actual lesion dimensions were larger than dimension estimates obtained with digital images (range, 23% to 35%) and film radiographs (range, 29% to 43%). Color-coded images were significantly less accurate than equalized images and unenhanced images. Images equalized through use of the measurement algorithm of the resident software provided estimates that were more accurate than estimates made with film radiographs and a standard millimeter rule. Intrarater variability was low. The application of color coding was found to be unreliable. CONCLUSIONS: When applied to intraoral images, color-coded image processing of digital images had limited value in the estimation of periradicular lesional dimensions.

Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine.

In the present paper we investigated, in the rat brain, the expression of basic fibroblast growth factor (FGF-2) in response to the atypical antipsychotic clozapine. We found that acute or chronic administration of this compound produced a selective increase of FGF-2 mRNA and protein in the striatum. Although acute injection of clozapine did increase FGF-2 expression in parietal cortex and nucleus accumbens we found that, following repeated administration, the induction of the trophic molecule was taking place only at striatal level. The analysis of other antipsychotic drugs did not provide conclusive evidence for the molecular mechanisms involved in clozapine-induced elevation of FGF-2. In fact, chronic administration of classical neuroleptics, haloperidol and chlorpromazine, did not alter the expression of FGF-2. Furthermore the novel drugs quetiapine and olanzapine, despite some similarities in their receptor profiles, were similarly ineffective. Hence these data suggest that, among antipsychotic drugs, the induction of FGF-2 is unique to clozapine. On the basis of the neuroprotective activity of this trophic molecule, our data might be relevant for the potential use of clozapine in tardive dyskinesia and parkinsonism, which develop during long term administration of classical neuroleptic drugs.

Cisapride: a survey of the frequency of use and adverse events in premature newborns.

OBJECTIVE: This survey estimated the frequency of use and adverse events associated with cisapride treatment of premature newborns in intensive care units. It was initiated in response to a warning issued in Canada cautioning against cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age. METHODOLOGY: Surveys were mailed to 105 neonatology training program directors to obtain the total number of neonatal intensive care unit (NICU) admissions, the number of admissions of infants of <36 weeks' gestation, the number of years that cisapride had been used, the estimated percent/number of premature patients treated with cisapride per year, and the frequency and nature of arrhythmias or other adverse events associated with cisapride treatment. Of 105 programs, 46 responded to a single mailing of the first survey. A second survey mailed to the 45 respondents to the first survey sought to determine the indications, diagnostic tests, and dosages used with cisapride treatment of premature newborns. Of the 45 programs, 26 responded to the second survey. RESULTS: More than 58 000 premature newborns of <36 weeks' gestation were admitted to the NICUs we surveyed, and approximately 19% were treated with cisapride. No deaths attributable to cisapride were reported among >11 000 preterm newborns treated. Three nonfatal arrhythmias were reported; two associated with 10-fold dosing errors and one with co-treatment with erythromycin, a macrolide antibiotic that reduces the metabolism of cisapride. Diarrhea was reported in 12 patients, and reversible liver enzyme changes were noted in one patient. Typically, cisapride treatment was started in dosages of 0.1 to 0.2 mg/kg/dose, repeated every 6 to 8 hours. Treatment usually was begun empirically, without a preceding study to document gastroesophageal reflux. The most frequent indications for cisapride treatment were choking or gagging, with associated apnea, bradycardia, and desaturation. Approximately 50% of patients had discontinued cisapride treatment before discharge. Eighty-four percent of clinicians judged cisapride to be effective for the problems being treated. CONCLUSIONS: Cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age in NICUs appears to be widespread in the United States. Complications and adverse events were seen when cisapride was administered in excessive dosages or in combination with a drug that inhibits its metabolism and leads to increased serum concentrations. Severe toxicities such as arrhythmias were reported with a frequency of <1/11 000 NICU admissions. However, in a retrospective survey, episodes of toxicity, including mortality, attributable to cisapride may not have been recognized or reported.

Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors.

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the numerous substances that originate from tobacco smoke, nicotine is by far the most widely studied. Nicotine is a natural alkaloid that has considerable stimulatory effects on the CNS. Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChRs, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)-nicotine in two animal models of parkinsonism: diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice and methamphetamine-induced neurotoxicity in rats and mice. The neuroprotective effect of (-)-nicotine was very similar to that of the noncompetitive NMDA receptor antagonist (+)-MK-801. In parallel experiments, we found that (-)-nicotine induces the basic fibroblast growth factor-2 (FGF-2) and the brain-derived neurotrophic factor in rat striatum. The effect of (-)-nicotine on the induction of FGF-2 was prevented by the nAChR antagonist mecamylamine. We also found that (+)-MK-801 was able to induce FGF-2 in the striatum. As trophic factors have been reported to be neuroprotective for dopaminergic cells, our data suggest that the increase in neurotrophic factors is a possible mechanism by which (-)-nicotine protects from experimental parkinsonisms.