Attenuation of ongoing neuropathic pain by peripheral acting opioid involves activation of central dopaminergic neurocircuitry.

BACKGROUND AND PURPOSE: Ongoing neuropathic pain is one of the most challenging clinical problems which have detrimental effects on a patient's life quality. Conventional therapies for chronic neuropathic pain majorly includes centrally acting analgesics. Unfortunately, the unceasing use of these drugs results in adverse effects, such as CNS in-coordination, respiratory depression and substance use disorder. DALDA ([D-Arg2, Lys4]-Dermorphin-(1-4)-amide), a peripherally acting opioid have been shown to possess potent analgesic activity without causing CNS toxicities in nerve-injured rats. However, the mechanism(s) underpinning DALDA induced-attenuation of ongoing neuropathic pain is yet to identify [1]. EXPERIMENTAL DESIGN: In this study, we have measured the in-silico ligand-receptor binding affinity of DALDA against potential inflammatory targets by utilizing glide module of schrödinger software. Effect of DALDA on oxido-inflammatory stress was evaluated in LPS-induced C6 glial cells. In-vitro studies were followed by the behavioral assessments, where effect of DALDA was measured in chronic constriction injured rats. To examine the effect of DALDA on dopaminergic neurotransmission, cerebrospinal fluid of nerve-injured rats was assessed using LC-MS/QToF (Liquid Chromatography-Mass spectrometry/ Quadrapole time of flight Analyzer). RESULTS: DALDA has shown a good binding affinity with chemokine receptor type-2 (CCR2), chemokine CX3C receptor 1 (CX3CR1) and purinergic receptor (P2×4), major receptor subtypes involved in pain and inflammation. Findings from the in-vitro studies suggest that DALDA possesses potent anti-oxidant activity leading to inhibition of p38-MAPK pathway [1]. Moreover, the subcutaneous administration of DALDA leads to dose-dependent attenuation of thermal and mechanical hypersensitivity along with inhibition of neuroinflammatory mediators in serum and spinal cord of nerve-injured rats. Most importantly, DALDA treated neuropathic rats showed a preference for the DALDA-treated chamber, which was attenuated on pre-treatment with dopaminergic receptor antagonist, flupenthixol. LC-MS analysis further confirms the enhanced dopaminergic transmission in the brain of DALDA-treated neuropathic rats. CONCLUSION: Our findings suggest that DALDA mediated attenuation of ongoing neuropathic pain may be associated with a decrease in spinal neuroinflammatory signalling and subsequent increase in the brain dopamine level; may serve a potential therapeutic for the treatment of ongoing neuropathic pain.

Ultra-selective fiber optic SPR platform for the sensing of dopamine in synthetic cerebrospinal fluid incorporating permselective nafion membrane and surface imprinted MWCNTs-PPy matrix.

Surface plasmon resonance (SPR) based dopamine sensor is realized using the state-of-art technique of molecular imprinting over an optical fiber substrate. Polypyrrole (PPy) is depicted as an effective polymer for the imprinting of dopamine through a green synthesis approach. Sensitivity of the probe is enhanced by the augmenting effect of surface imprinting of dopamine in polypyrrole over multiwalled carbon nanotubes (MWCNTs). To ensure the permselectivity of the probe towards dopamine molecules, a cation exchange polymer, nafion, is utilized as a membrane over imprinted sites to reduce the interference from anionic analytes like ascorbic acid and uric acid at physiological pH. The probe is characterized for a wide range of dopamine concentration from 0 to 10-5 M in artificial cerebrospinal fluid. Various probe parameters are varied to maximize the sensitivity of the sensor. The sensor possesses 18.9 pM as the limit of detection (LOD) which is lowest of those reported in the literature. The manifestation of sensing probe over an optical fiber along with the improved LOD makes the approach highly advantageous in terms of stability, repeatability, online remote monitoring, fast response, and miniaturization for its in vivo/in vitro applications in clinical sensing of dopamine.

Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies.

INTRODUCTION: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients. METHODS: CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32). RESULTS: Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 ± 0.02 and 0.13 ± 0.02 vs. 0.05 ± 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 ± 0.01). CONCLUSIONS: CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism.

Excessive Iron and α-Synuclein Oligomer in Brain are Relevant to Pure Apathy in Parkinson Disease.

OBJECTIVES: To investigate the demographic features, clinical features, and potential mechanism in patients with Parkinson disease (PD) with pure apathy. METHOD: A total of 145 patients with PD without depression and dementia and 30 age-matched controls were consecutively recruited. Patients with PD were evaluated by Apathy Scale (AS), scales for motor symptoms and quality of life. The levels of iron, oxidative and neuroinflammatory factors, α-synuclein oligomer, and dopamine in cerebrospinal fluid (CSF) from patients with PD and controls were detected by enzyme-linked immunosorbent assay, chemical colorimetric method, and high-performance liquid chromatography. Comparisons between PD with pure apathy and with no pure apathy groups and correlation between AS score and the levels of above factors were analyzed. RESULTS: There were 64 (44.14%) cases in PD-apathy group. The PD-apathy group had older age, (97.81 ± 10.82) years versus (61.86 ± 10.80) years, and severer quality of life (P < .05). The PD-apathy and PD without apathy groups presented no remarkable differences in motor symptoms (P > .05). The levels of iron, hydroxyl radical (·OH), hydrogen peroxide (H2O2), and α-synuclein oligomer in CSF in PD-apathy group were significantly higher than that in PD without the apathy group (P < .05). In patients with PD, the AS score was positively correlated with the levels of iron, ·OH, H2O2 and α-synuclein oligomer in CSF (r = 19.838, .063, 1.046, and 0.498, respectively, P < .05). In PD-apathy group, iron level was positively correlated with ·OH level (r = .011, P < .05), and H2O2 level was positively correlated with α-synuclein oligomer level in CSF (r = .045, P < .05). CONCLUSION: Patients with PD had high prevalence of pure apathy. Patients with PD having pure apathy had older age. Pure apathy reduced quality of life for patients without worsening motor function. Excessive iron and α-synuclein oligomer in brain commonly contributed to pure apathy of PD through potential mechanism of oxidative stress.

Cerebrospinal fluid inflammatory cytokines and aggression in personality disordered subjects.

BACKGROUND: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression-facilitating role for central cytokines, especially for interleukin-1ß and other cytokines, no cerebrospinal fluid studies of cytokines have yet been reported in regard to human aggression. METHODS: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder and assayed for cerebrospinal fluid interleukin-6 (log IL-6) and cerebrospinal fluid soluble IL-1 Receptor II protein in the context of their relationship with measures of aggression. RESULTS: Cerebrospinal fluid soluble interleukin-1 Receptor II (r=.35, r(2) = .12, P= .03), but not log interleukin-6 (r = -.05, r(2) = .00, P= .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including cerebrospinal fluid levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, P= .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality. CONCLUSION: These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects.

Monoamine metabolites in ventricular CSF of children with posterior fossa tumors: correlation with tumor histology and cognitive functioning.

OBJECT: The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning. METHODS: Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital "Agia Sofia" were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC). RESULTS: Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum. CONCLUSIONS: This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.

Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n=25) compared to controls (n=9), and were negatively correlated with CSF DA (r=-0.59, df=15, p<0.05) and its metabolite, homovanillic acid (r=-0.67, df=15, p<0.01), and positively correlated with fatigue (r=0.44, df=23, p<.05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n=12) compared to controls (n=7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r=-0.57, df=12, p<0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response.

Recent advances in CSF biomarkers for Parkinson's disease.

Though the search for cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD) began more than 40 years ago, the most promising results are relatively recent. Disease-specific indicators have been sought among the hundreds of proteins and other biochemicals found in CSF (which is contiguous with the extracellular fluid compartment of the brain). Initially, research focused on the selective neurotransmitter disturbance in PD. While investigations of dopamine metabolism (as reflected by its major metabolite, homovanillic acid [HVA]) have been relatively uninformative, we found that indexing HVA concentration to that of the purine metabolite xanthine permits differentiation of PD specimens from healthy controls (p < 0.0016) [Brain Research 2011;1408:88-97]. In another recent biomarker study, we utilized ultrahigh-performance liquid chromatography linked to gas chromatography-mass spectrometry for metabolomic analysis [Movement Disorders 2011;26(Suppl 2):S193]. Using t-tests to differentiate PD and control groups at p < 0.02, we found changes in compounds not known to be related to the neurodegenerative process (4 increased in CSF concentration and 8 decreased). Other recent investigations have reported distinctive biomarker findings in proteins and other biochemicals. The ultimate goal is for CSF biomarkers also found in peripheral biospecimens, aiding in diagnostic screening applications and providing further clues as to the etiology of PD.

Determination of dopamine, serotonin, and their metabolites in pediatric cerebrospinal fluid by isocratic high performance liquid chromatography coupled with electrochemical detection.

A method to rapidly measure dopamine (DA), dihydroxyindolphenylacetic acid, homovanillic acid, serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations in cerebrospinal fluid (CSF) has not yet been reported. A rapid, sensitive, and specific HPLC method was therefore developed using electrochemical detection. CSF was mixed with an antioxidant solution prior to freezing to prevent neurotransmitter degradation. Separation of the five analytes was obtained on an ESA MD-150 x 3.2 mm column with a flow rate of 0.37 mL/min and an acetonitrile-aqueous (5 : 95, v/v) mobile phase with 75 mM monobasic sodium phosphate buffer, 0.5 mM EDTA, 0.81 mM sodium octylsulfonate and 5% tetrahydrofuran. The optimal electrical potential settings were: guard cell +325 mV, E1 -100 mV and E2 +300 mV. Within-day and between-day precisions were <10% for all analytes and accuracies ranged from 91.0 to 106.7%. DA, 5-HT, and their metabolites were stable in CSF with antioxidant solution at 4 degrees C for 8 h in the autoinjector. This method was used to measure neurotransmitters in CSF obtained from children enrolled on an institutional medulloblastoma treatment protocol.

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys.

Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements. As the infants grew, they were all screened with hematological tests, which documented that 16 (33.3%) became markedly ID between 4 and 8 months of age. During this anemic period and subsequently at 1 year of age, cerebrospinal fluid (CSF) specimens were collected to compare monoamine activity in the ID and iron-sufficient infants. Monoamine neurotransmitters and metabolite levels were normal at 4 and 8 months of age, but by 1 year the formerly anemic monkeys had significantly lower dopamine and significantly higher norepinephrine levels. These findings indicate that ID can affect the developmental trajectory of these two important neurotransmitter systems, which are associated with emotionality and behavioral performance, and further that the impact in the young monkey was most evident during the period of recovery.

Perioperative concentrations of catecholamines in the cerebrospinal fluid and plasma during spinal anesthesia.

BACKGROUND: Catecholamine release is a physiological response to stress. The extent to which perioperative stress provokes the central release of catecholamines, which modulate pain perception in the spinal cord, still remains unknown. The perioperative course of catecholamine concentrations in the cerebrospinal fluid (CSF) and plasma was examined. METHODS: A prospective study was performed in 25 patients (ASA III, 60-84 years) undergoing elective hip joint replacement in spinal catheter anesthesia. The concentrations of dopamine, epinephrine and norepinephrine in the CSF and plasma were measured before anesthesia, immediately after surgery, and 6 and 24 h post-operatively. RESULTS: In most patients, dopamine and epinephrine were not detectable in CSF. CSF-norepinephrine concentrations decreased from median [interquartile-range] 159 [124;216] pre-anesthesia to 116 [79;152] pmol/l immediately post-operatively and were slightly elevated 24 h post-operatively (180 [134;302] pmol/l) (P=0.05). Dopamine plasma concentrations were not detectable or were barely above the detection threshold. Plasma epinephrine increased from 61 [28;77] pmol/l pre-anesthesia to 112 [69;138] pmol/l 6 h post-operatively and returned to baseline 24 h post-operatively (P=0.001). Plasma norepinephrine concentrations increased intra-operatively from 298 [249;422] to 556 [423;649] pmol/l and remained elevated 24 h after surgery (P=0.009). There was no association between changes in CSF or plasma norepinephrine or epinephrine concentrations and changes in heart rate (HR) or mean arterial pressure (MAP). CONCLUSION: During spinal anesthesia for elective hip joint replacement, norepinephrine concentrations were greater in plasma than in CSF. CSF dopamine and epinephrine concentrations were essentially undetectable. The changes in CSF-norepinephrine concentrations and the changes of plasma norepinephrine concentrations showed no association with each other; nor were there correlations between clinical stress parameters (HR, MAP) or visual analog scale pain, and the changes in CSF norepinephrine concentrations.

Control of dopamine-secretion by Tet-Off system in an in vivo model of parkinsonian rat.

We established a PC12 cell line (PC12TH Tet-Off) in which human tyrosine hydroxylase (TH) expression can be negatively controlled by Doxycycline (Dox). First, dopamine (DA)-secretion from PC12TH Tet-Off cells was controlled by Dox-administration in a dose-responsive manner ranging from 0 to 100 ng/ml for 70 days in vitro. Furthermore, Parkinson's disease model of rats receiving encapsulated PC12TH Tet-Off cells displayed a significant decrease of dopamine concentration in the cerebrospinal fluid (CSF) and increase of the number of apomorphine-induced rotations by Dox-administration, as compared to transplanted rats without Dox-administration, although the significant decrease of the reduction ratio of DA concentration in the CSF with Dox-administration was recognized over time. At 2 months post-implantation, concentration of dopamine in the implanted striatum and from the retrieved capsules demonstrated that the control of DA-secretion could be partially achieved for 2 months in vivo. Our results support both the value of cell therapy using Tet-Off system and the technique of encapsulation might be a feasible option for Parkinson's disease especially in resolving the problem of dopamine oversupply in the future, although a more efficient way to control DA-secretion with quicker regulation and much titration of dose should be explored before clinical application.

Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

Elevated 5-S-cysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid in cerebrospinal fluid: possible markers for and potential insights into the pathoetiology of Parkinson's disease.

High-performance liquid chromatography with electrochemical detection has been employed to analyze ultrafiltrates of cerebrospinal fluid of Parkinson's Disease (PD) patients and age-matched controls for the dopamine (DA) metabolites homovanillic acid (HVA) and 5-S-cysteinyldopamine (5-S-CyS-DA). The mean level of HVA in the CSF of PD patients, measured 5 days after withdrawal from L-DOPA therapy, was significantly lower than that measured in controls. By contrast, mean levels of 5-S-CyS-DA were not significantly different in the CSF of PD patients taking L-DOPA (PD-LT patients) the same patients 5 days after discontinuing this drug (PD-LW patients) or controls. However, the mean 5-S-CyS-DA/HVA concentration ratio was significantly (p < 0.05) higher in the CSF of PD-LW patients compared to controls. Although the PD patient population employed in this study had been diagnosed with the disease several years previously and had been treated with L-DOPA for prolonged periods of time the results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of PD. The high 5-S-CyS-DA/HVA ratio observed in the CSF of PD-LW patients also provides support for the hypothesis that the translocation of glutathione or L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra might represent an early event in the pathogenesis of PD.

Separación de aminas biogénicas mediante cromatografía líquida de alta resolución / High-performance liquid chromatographic determination of biogenic amines

En este trabajo se han compilado los distintos modos cromatográficos y sistemas de detección utilizados en la cromatografía líquida de alta resolución de aminas biogénicas. Se indican las características generales del intercambio catiónico, fase reversa, fase reversa de pares iónicos y cromatografía de partición con fase reversa de pares iónicos. También se analizan comparativamente la detección UV, detección fluorimétrica usando fluorescencia nativa o bien derivatización pre- y postcolumna y detección electroquímica de gran utilidad para esta extensa familia de compuestos. Se dan ejemplos de aplicación de interés en el campo bioquímico-clínico, con el análisis de ácido homovainillínico, ácido 3,4-dihidroxifenilacético y ácido 5-hidroxiindolacético en líquido cefalorraquídeo, metanefrinas, ácido 3,4-dihidroxifenilacético, catecolaminas, ácidos urinarios y 3-metoxi-4-hidroxifenilglicol en orina, catecolaminas y 3-metoxi-4-hidroxifenilglicol en plasma, catecolaminas, 3-metoxi-4-hidroxifenilglicol y otros neurotransmisores en cerebro de rata. Se discuten, también, los tratamientos previos requeridos especialmente para orina y plasma, así como las condiciones de conservación y su incidencia en los resultados obtenidos

Does dantrolene influence central dopamine and serotonin metabolism in the neuroleptic malignant syndrome? A retrospective study.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) were determined twice in nine cases of neuroleptic malignant syndrome (NMS) during the active phase. During the test period, three cases received no dantrolene and six cases received dantrolene prior to the second CSF examination. In the group not administered dantrolene, the levels of HVA and 5-HIAA were lower on the second examination compared to the first, suggesting that the levels of these substances decreased during the course of NMS. In the group receiving dantrolene, the levels of HVA and 5-HIAA increased after administration compared with the preadministration levels. In particular, a significant difference in the changes in HVA was demonstrated between the two groups. This suggests that dantrolene influences central dopaminergic metabolism in the active phase of NMS.

[Transplantation of fetal adrenal medullary to the brain in Parkinson's disease].

The adrenal medullary tissue removed from the fetus donor aborted at the age of 24 weeks was cultured for one week. Approximately 200-300 mg tissue was placed at the head of bilateral caudate in 17 severe patients with PD. Follow-up lasted for 3 to 18 months. Improvement was observed in all patients 3 months after grafting. Clinical analysis showed that the efficacy was significant and that one of the 17 patients relapsed. The response rate of 6 to 12 months was 87.5%. Immediately after operation, the drug was withheld or decreased in dosage. The low density areas in the head of caudate nucleus was found by CT within 1 to 10 days, and disappeared one month after operation. We conclude that the human fetal adrenal medullary tissue can survive in the human brain and is associated with functional effect. Transplantation of the brain tissue is useful in the treatment of PD.

Catechol metabolites in the cerebrospinal fluid as possible markers in the early diagnosis of Parkinson's disease.

This paper is a preliminary report of work aiming to elucidate the possible use of 5-S-cysteinyl metabolites of catechols in the cerebrospinal fluid as markers in the early diagnosis of Parkinson's disease (PD). The rationale for this approach is the hypothesis that this disorder is caused by a failure of antioxidative mechanisms to prevent the excessive autoxidation of dopamine and other catechols that yields highly reactive and cytotoxic semiquinones and quinones. 5-S-cysteinyl adducts of these quinones have been detected in human brains, analyzed postmortem, and appear to be formed at an increased rate in elderly individuals, who show an increased loss of dopaminergic neurons.

Adrenal medullary transplants increase spinal cord cerebrospinal fluid catecholamine levels and reduce pain sensitivity.

Previous work in this laboratory has shown that adrenal medullary transplants into the spinal cord subarachnoid space can reduce pain sensitivity. This analgesia most likely results from the release of neuroactive substances, particularly catecholamines and opioid peptides, from the transplanted cells into the CSF of the spinal cord, since it can be attenuated or blocked by alpha-adrenergic or opiate antagonists. The purpose of the present study was to more directly measure the release of catecholamines from adrenal medullary transplants in the spinal cord CSF using a spinal superfusion technique. CSF samples from rats with 6-month-old transplants were assayed for catecholamines using HPLC with electro-chemical detection. Results indicated that norepinephrine levels were increased threefold, and epinephrine levels nearly 100-fold, in animals with adrenal medullary transplants compared with control transplanted animals. There was no apparent increase in dopamine levels. Furthermore, the increased levels of total catecholamines were correlated with decreased pain sensitivity. Results of this study indicate that adrenal medullary transplants can survive for long periods in the rat spinal CSF and continue to release high levels of catecholamines. Together, the release of catecholamines and opioid peptides from adrenal medullary transplants may provide the ideal combination for the reduction of pain.