Fang-Chia Chang

Blockade of corticotropin-releasing hormone receptors reduces spontaneous waking in the rat

We have previously hypothesized that corticotropin-releasing hormone (CRH) is involved in the regulation of physiological waking. To further elucidate this role for CRH, we administered intracerebroventricularly into rats two specific CRH-receptor antagonists, α-helical CRH-(9-41) (α-hCRH) or astressin, and determined changes in electroencephalogram-defined waking and sleep. Our results indicate that both of these receptor antagonists reduce the amount of time spent awake in a dose-related manner when administered before the dark period of the light-dark cycle. However, the time courses for these effects differ between antagonists; effective doses of α-hCRH reduce waking during the first 2 h postinjection, whereas effective doses of astressin reduce waking during postinjection hours 7-12. In contrast to dark-onset administrations, the amount of waking is not altered by either CRH-receptor antagonist when administered before the light period. These results support our hypothesis that CRH contributes to the regulation of physiological waking, since interfering with the binding of CRH to its receptor reduces spontaneous waking.

The Central Serotonergic System Mediates the Analgesic Effect of Electroacupuncture on Zusanli (ST36) Acupoints

Evidence in the past decade indicates that the mechanisms of anti-nociception of electroacupuncture (EAc) involve actions of neuropeptides (i.e., enkephalin and endorphin) and monoamines (i.e., serotonin and norepinephrine) in the central nervous system. Our present results using a subcutaneous injection of formalin to test pain sensation in mice provide further understanding of the involvement of serotonin in the actions of EAc-induced analgesia. Our observations show that (1) EAc at three different frequencies (2, 10 and 100 Hz) elicited an anti-nociceptive effect as determined by behavioral observations of reduced hindpaw licking; (2) exogenously intracerebroventricular administration of 5-hydroxytryptamine (5-HT) exhibited an analgesic effect, which partially mimicked the analgesic actions of EAc; (3) the anti-nociception of EAc at different frequencies was attenuated after reduced biosynthesis of serotonin by the administration of the tryptophan hydroxylase inhibitor, P-chlorophenylalanine, and (4) the 5-HT(1A) and 5-HT(3) receptor antagonists, pindobind-5-HT(1A) and LY-278584, respectively, blocked three different frequencies of EAc-induced analgesic effects, but the anti-nociceptive effect of 100 Hz EAc was potentiated by the 5-HT(2) receptor antagonist, ketanserin. These observations suggest that 5-HT(1A) and 5-HT(3) receptors partially mediate the analgesic effects of EAc, but that the 5-HT(2) receptor is conversely involved in the nociceptive response.

Corticotropin-releasing hormone (CRH) as a regulator of waking.

Corticotropin-releasing hormone (CRH), expressed in widely distributed regions of the central nervous system (CNS), mediates the hypothalamic-pituitary-adrenal (HPA) axis and autonomic components of responses to stressors. Sleep, a fundamental CNS process, is altered in response to a variety of stressors. Although there is an extensive literature on the role of CRH in responses to stressors, there is relatively little information on the role of CRH in normal, spontaneous behavior. We hypothesize that CRH is involved in the regulation of waking in the absence of overt stressors. Some of the early evidence supporting this hypothesis was indirect. We summarize in this review studies from our laboratory and others that provide direct evidence that CRH is involved in the regulation of spontaneous waking. We also suggest on the basis of recent studies that some effects of CRH on waking and sleep may be mediated by actions within the CNS of the immunomodulatory cytokine interleukin (IL)-1. Collectively, these observations suggest that CRH contributes to the regulation of spontaneous waking in the absence of stressors, and also indicate a potential mechanism mediating complex alterations in sleep that occur in response to immune challenge.

Environmental risk factors of young onset Parkinson's disease: a case-control study

While the cause of Parkinsons disease (PD) remains unknown, recent evidence suggests certain environmental factors, such as well water drinking, herbicides and pesticides exposure, and neurotoxins, may trigger the chain of oxidative reactions culminating in the death of dopaminergic neurons in substantia nigra to cause parkinsonism. Most studies to date focused on PD with old age onset. However, there is a peculiar group of parkinsonian patients, the young onset Parkinsons disease (YOPD), in whom the age of onset is before 40. It is intriguing to know whether earlier exposure to the putative neurotoxin(s) may contribute to the earlier onset. We therefore conducted this case-control study in which 60 PD patients, 30 YOPD patients and the same number of age- and sex-matched young controls were included. Using logistic regression, we found well water drinking and head injury were risk factors for the development of YOPD. When YOPD patients were compared with PD, we found head injury and exercise were the significant predictors. Keeping all other variables constant, head injury was a risk factor and exercise appeared to be a protective factor. We conclude early exposure to well water drinking and head trauma may trigger and expedite the appearance of parkinsonian features, but such acceleration may be prevented through regular exercise.

A corticotropin-releasing hormone antisense oligodeoxynucleotide reduces spontaneous waking in the rat

We have previously hypothesized that corticotropin-releasing hormone (CRH) is involved in the regulation of physiological waking. In this study, we tested the hypothesis that reduction of CRH peptide would reduce spontaneous wakefulness of rats. We administered intracerebroventricularly into rats at several circadian time points antisense or sense DNA oligodeoxynucleotides (ODNs) corresponding to the initiation codon of CRH mRNA and determined subsequent effects on wakefulness and sleep of the rat. Our results indicate that CRH antisense oligodeoxynucleotides reduce spontaneous wakefulness during the dark (active) period, but not during the light (rest) period of the light/dark cycle. The alterations in time spent awake are due to reduced wake bout numbers, rather than a change in wake bout duration. These reductions in wakefulness were mirrored by increases in slow-wave sleep, while rapid eye movement sleep was not affected. Corticosterone, used as an index of CRH in the hypothalamus, was reduced by CRH antisense oligodeoxynucleotides during the same time that spontaneous wakefulness was reduced, suggesting CRH peptide modulation as the mediator of this response. In contrast, CRH sense oligodeoxynucleotides did not alter any parameter of this study during either the dark or light period. These findings provide additional support for the hypothesis that CRH is involved in the regulation/modulation of wakefulness.

Two novel mutations of the glycine receptor gene in a Taiwanese hyperekplexia family

The authors report a Taiwanese family with autosomal recessive hyperekplexia. Two novel mutations, W96C (from the paternal allele) and R344X (from the maternal allele), which are located in exon 4 and exon 7 of the GLRA1 gene, were identified in this family. A series of electrophysiologic investigations were conducted in one of the probands, and the results suggest that the “startle center” is located subcortically.

Endogenous Opiates in the Nucleus Tractus Solitarius Mediate Electroacupuncture-Induced Sleep Activities in Rats

Electroacupuncture (EA) possesses various therapeutic effects, including alleviation of pain, reduction of inflammation and improvement of sleep disturbance. The mechanisms of EA on sleep improvement, however, remain to be determined. It has been stated in ancient Chinese literature that the Anmian (EX17) acupoint is one of the trigger points that alleviates insomnia. We previously demonstrated that EA stimulation of Anmian acupoints in rats during the dark period enhances non-rapid eye movement (NREM) sleep, which involves the induction of cholinergic activity in the nucleus tractus solitarius (NTS). In addition to cholinergic activation of the NTS, activation of the endogenous opioidergic system may also be a mechanism by which acupuncture affects sleep. Therefore, this study was designed to investigate the involvement of the NTS opioidergic system in EA-induced alterations in sleep. Our present results indicate that EA of Anmian acupoints increased NREM sleep, but not rapid eye movement sleep, during the dark period in rats. This enhancement in NREM sleep was dose-dependently blocked by microinjection of opioid receptor antagonist, naloxone, and the μ-opioid receptor antagonist, naloxonazine, into the NTS; administrations of δ-receptor antagonist, natrindole, and the κ-receptor antagonist, nor-binaltrophimine, however, did not affect EA-induced alterations in sleep. Furthermore, β-endorphin was significantly increased in both the brainstem and hippocampus after the EA stimuli, an effect blocked by administration of the muscarinic antagonist scopolamine into the NTS. Our findings suggest that mechanisms of EA-induced NREM sleep enhancement may be mediated, in part, by cholinergic activation, stimulation of the opiodergic neurons to increase the concentrations of β-endorphin and the involvement of the μ-opioid receptors.

Pituitary CRH receptor blockade reduces waking in the rat.

We have previously hypothesized that corticotropin-releasing hormone (CRH) is involved in the regulation of physiological waking. Central administration of CRH receptor antagonists reduces spontaneous waking in the rat. Some of the responses to central administration of CRH receptor antagonists may be mediated by mechanisms involving the hypothalamic-pituitary-adrenal axis, either by direct actions on the hypothalamus or by actions at the level of the pituitary due to leakage of the antagonists from the cerebrospinal fluid to blood. To further clarify the role of the hypothalamic-pituitary-adrenal axis as a mediator of responses to CRH receptor blockade, we administered intravenously into freely behaving rats in their home recording cages two specific CRH receptor antagonists, astressin or alpha-helical CRH, and determined subsequent changes in waking and sleep. Our results indicate that both antagonists reduce spontaneous waking, but with different time courses. Astressin, a potent antagonist of pituitary CRH receptors, reduces waking during postinjection hours 9-10, whereas high doses of alpha-helical CRH reduce waking only during the first postinjection hour. These results indicate that some effects of CRH on sleep-wake behavior may be meditated by pituitary CRH receptors.

Epileptiform activity induced by 4-aminopyridine in rat amygdala neurons: the involvement of N-methyl-D-aspartate receptors

The involvement of the N-methyl-D-aspartate (NMDA) receptor in the epileptiform activity induced by 4-aminopyridine (4-AP) was studied in rat amygdala slices using intracellular recording techniques. Stimulation of the ventral endopyriform nucleus evoked an excitatory postsynaptic potential (EPSP). After exposure to 4-AP (200 microM) the amygdala slices usually exhibited spontaneous and evoked epileptiform activity. The epileptiform events had an average duration of 522 +/- 78 ms with a frequency of 0.5-8.5 bursts/min. Superfusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-NMDA receptor antagonist, practically abolished the epileptiform bursting. However, there remained a residual depolarizing component in 13 out of 18 neurons. This CNQX-resistant component was markedly enhanced both in amplitude and duration when extracellular Mg2+ was removed and could be reversibly blocked by the specific NMDA receptor antagonist, DL-2-amino-5-phosphonovaleate (DL-APV). Compared with the CNQX-sensitive component, the APV-sensitive component had a much smaller amplitude shorter duration. These data suggest that the NMDA receptor is likely to play only a minor role, and activation of the NMDA receptor may contribute to but is not required, for the generation of these bursts.

Reversible paraneoplastic limbic encephalitis caused by a benign ovarian teratoma: report of a case and review of literatures

Paraneoplastic limbic encephalitis (PLE) is widely believed to be a remote, irreversible neurological complication of small cell lung carcinoma and other malignancies [1]. PLE caused by a mature ovarian teratoma is extremely rare; in fact, only three cases have been reported [2–4]. We report a patient with a reversible PLE caused by a benign ovarian teratoma. A 35-year-old married saleswoman had been well until October 2001 when she had one episode of tonic deviation of the tongue toward left cheek followed by numbness of the left-sided of her face and clonic convulsion of both upper limbs. These symptoms lasted for approximately 2 min before completely resolving. She went to work as usual the next day. However, 3 days after the neurological insult, she was hospitalized because of fluctuating paraesthesia of the left-sided of her face and the right lower limb. Physical and neurological examinations revealed a large palpable mass in the pelvic region. Two days after admission, bursts of agitation, irritation, confusion, and focal seizures developed. After initial conservative treatment, the patient’s condition deteriorated rapidly. Inattention, incoherent speech, hand tremor, dystonia, and sweating were noted. Furthermore, her blood pressure and heart beats were in fulminant fluctuation. A brain MRI preand post-gadolinium on 10 October, 2001 was normal. Electroencephalograms (EEG) on 29 October, 2001 and November 5, 2001 disclosed diffuse, continuous delta and theta waves with intermittent sharp-wave complexes in both frontal lobes. A HMPAO SPECT 1 week after admission in 2001 revealed regional cerebral hypoperfusion involving both frontal lobes and the left temporal lobe. A lumbar puncture yielded clear CSF under normal pressure containing 9 white counts per microliter, 75 mg/dl of glucose, and 18 mg/dl of protein. The bacterial and TB cultures for microorganisms, cryptococcal antigen test, venereal disease research laboratory test, and the herpes simplex virus PCR of the CSF were negative. No malignant cells were identified by the CSF cytological examination. Serum complete blood cell counts disclosed anemia (Hb: 11 gm/dl). The results from the following serologic tests of erythrocyte sedimentation rate, blood ammonia, thyroid function, vitamin B12, and folic acid were within normal range. Antinuclear Antibody test, HIV antibody, and anti-Japanese B virus antibody were negative. Serum immunoglobulin levels, including IgG, IgA, IgM, C3, and C4, were also within normal range. A mildly elevated serum tumor marker CA-125 [50.04 U/ml ( <35)] was noted. Pelvic Y.-W. Yang Æ C.-H. Tsai Æ F.-C. Chang Æ M.-K. Lu Department of Neurology, Neuroscience Laboratory, China Medical University Hospital, Taichung, Taiwan