Dexmedetomidine and propofol sedation requirements in an autistic rat model / 대한마취과학회지

BACKGROUND: Autism is a challenging neurodevelopmental disorder. Previous clinical observations have suggested altered sedation requirements for children with autism. Our study aimed to test this observation experimentally in an animal model and to explore its possible mechanisms. METHODS: Eight adult pregnant female Sprague-Dawley rats were randomly divided into two groups. Four were injected with intraperitoneal sodium valproate on gestational day 12 and four were injected with normal saline. On postnatal day 28, the newborn male rats were subjected to the open-field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). The times to loss of righting reflex (LORR) and to return of righting reflex (RORR) were recorded. On the following day, all rats were re-sedated and underwent electroencephalography (EEG). Thereafter, the rats were euthanized and their hippocampal gamma-aminobutyric acid type A (GABA(A)) and glutamate N-methyl-D-aspartate (NMDA) receptor gene expressions were assessed. RESULTS: Autistic rats showed significantly longer LORR times and shorter RORR times than did the controls (median LORR times: 12.0 versus 5.0 min for dexmedetomidine and 22.0 versus 8.0 min for propofol; P < 0.05). EEG showed a low-frequency, high-amplitude wave pattern 2 min after LORR in the control rats. Autistic rats showed a high-frequency, low-amplitude awake pattern. Hippocampal GABA(A) receptor gene expression was significantly lower and NMDA gene expression was greater in autistic rats. CONCLUSIONS: This study supports the clinical observations of increased anesthetic sedative requirements in children with autism and our biochemical analyses using and glutamate receptor gene expression highlight possible underlying mechanisms.

Homeopathic drugs complementary, antidotal and inimical to Nux vomica produce stronger anti-alcoholic effect on toads than Nux

In homeopathy some drugs are known to act as complementary, antidotal or inimical to a particular drug. Practitioners can follow this rule when they apply one drug following another. Potentized Nux vomica can reduce acute hypnotic effect of alcohol on toads. Sulphur and Sepia are reported to be complementary to Nux-vom, while Coffea cruda and Zincum met are antidotal and inimical to Nux, respectively [...] Methods: Five batches of toads, each comprising 20 individuals, were treated by partial immersion in a drug diluted with distilled water 1:500 for 20 min. The control consisted of 90% ethanol diluted with distilled water 1:500. The drugs were Nux vom 200 CH, Sulphur 200 CH, Sepia 200 CH, Coffea 200 CH and Zincum 200 CH. Toads of each batch were separately exposed to 260mM ethanol solution and tested every 10 min to see if they had lost their righting reflex (RR)[...] Results: Toads treated with the five drugs took significantly longer time (P<0.01, one-way ANOVA) to lose RR than those treated with the control. The time taken to lose RR was significantly longer (P<0.01, one-way ANOVA) with Sulphur 200 CH, Sepia 200 CH, Coffea 200 CH and Zincum 200 CH than with Nux vom 200 CH alone. The situation was same when Nux treatment was followed by each of the four drugs. Of the five drugs Coffea showed the strongest anti-hypnotic effect. Conclusion: 1. Drugs complementary, antidotal and inimical to Nux vom showed the same anti-alcoholic effect as Nux in terms of increased tolerance to alcohol anesthesia. 2. The anti-alcoholic effect of Nux vom was markedly superseded by the above four drugs. 3. Of all the drugs tested Coffea showed the strongest anti-alcoholic effect. 4. It appears that the above four drugs produced their individual dominant effect cancelling the individual effect of Nux vom.

Transfer of anti-alcoholic effect of Nux Vomica 200 cH through water from one group of toads to another under alcohol anesthesia

Background: A common practice is to give homeopathic medication to nursing mothers to treat their children, assuming that the drug will be conveyed by the milk. In the case of conventional treatment, the drug molecules are indeed passed on from the mother to her breastfed infant. However, high dilutions (HD) above 12 cH, i.e., over Avogadro’s number, are traditionally held to lack any molecule from the starting material. If that is the case, then, does medication taken by the mother actually reach the child? To answer to that question, we developed plant models and demonstrated the transfer of HD effects between 2 groups of plants. Aims: To demonstrate the transfer of HD effects in an animal model in a much shorter time. Methods: Two batches of toads were respectively placed in two beakers, one containing Nux vomica 200 cH diluted with water 1:500 (direct treatment), and the other the same amount of distilled water were connected by cotton thread soaked in water and encased in a polyethylene tube (connected group); a third batch of toads (control) were placed in a beaker with 90% ethanol diluted with distilled water 1:500; all the animals were left 30 minutes, and then transferred to 3 independent beakers containing 209 mM ethanol. Every 10 minutes, the motionless toads were removed from the beakers, and placed on supine position, failure to recover the upright position after 60 sec was considered as loss of the righting reflex (RR). The experiment was replicated using large adult toads. Results: The percentage of toads losing the RR increased with the time of exposure to 209 mM ethanol in the 3 groups of toads ... Conclusion: Nux-v 200 cH countered the hypnotic effect of alcohol in young toads, and this effect was transferred through capillary water in the cotton thread, supporting the transfer of the effect of homeopathic medication from mother to child.

Introdução: A prescrição de medicamentos homeopáticos às mães de lactentes é uma prática habitual, sob o pressuposto de que a droga é transmitida pelo leite materno. No caso do tratamento convencional, moléculas da droga são efetivamente transmitidas de mãe para filho. Porém, tradicionalmente se considera que altas diluições (AD) acima da 12 cH, ou seja, acima do número de Avogadro, não conservam qualquer molécula da substância original. Nesse caso, será que a medicação tomada pela mãe alcança realmente a criança? Para responder essa questão, desenvolvemos um modelo animal e demonstramos a transferência dos efeitos de AD entre 2 grupos de animais. Objetivos: Demonstrar a transferência dos efeitos de AD num modelo animal, num período de tempo mais breve. Métodos: Dois lotes de sapos foram respectivamente colocados durante 30 minutos em 2 béqueres, um contendo Nux vomica 200 cH diluído 1:500 em água destilada (tratamento direto) e o outro, a mesma quantidade de água destilada (grupo conectado) conectados através de fio de algodão molhado com água e coberto por um tubo de polietileno; um terceiro grupo de sapos (controle) foi colocado num béquer com solução de etanol 90% em água destilada. Os animais foram após transferidos para 3 béqueres, respectivamente, contendo etanol a 209 mM. A cada 10 minutos, os sapos imóveis eram removidos dos béqueres e colocados em posição supina. Aqueles que não recuperaram a posição ereta em até 60 segundos foram considerados como tendo perdido o reflexo de endireitamento (RE). O experimento foi replicado com sapos adultos. Resultados: A percentagem de sapos que perderam o RR aumentou com o tempo de exposição ao álcool, nos 3 grupos... Conclusão: Nux-v 200 cH inibiu o efeito hipnótico do álcool nos sapos, e este efeito foi transmitido pela água capilar no fio de algodão, dando suporte à hipótese de que o efeito dos medicamentos homeopáticos é transferido da mãe para o filho.

Comparative study on acute toxicity of four extracts from Xanthii Fructus in mice / 中国中药杂志

<p><b>OBJECTIVE</b>To comparative study the acute toxicity of four extracts from Xanthii Fructus in mice.</p><p><b>METHOD</b>Observed the toxic manifestations in mice which were given the four extracts by intragastric administration and calculated the LD50 of the four extracts from Xanthii Fructus.</p><p><b>RESULT</b>The toxic manifestations of the mice given water extract by intragastric administration were repose, pilo-erection, cyanosis, intention tremor, respiratory inhibition, loss of righting reflex and convulsion . The toxic manifestations of the mice given ethanol extract by intragastric administration were repose, abdominal respiration, intention tremor, intermittent convulsions, incontinence. The LD50 of Xanthii Fructus processed water extract, processed ethanol extract, crude water extract, crude ethanol extract were material drug 155.93, 317.80, 167.6, 275.41 g x kg(-1), respectively.</p><p><b>CONCLUSION</b>The acute toxicity of water extract is distinctly stronger than that of ethanol extract, but there is no marked distinguish between crude and processed extract.</p>

Experimental Models of Cerebral Palsy in Infant Rats / 한국실험동물학회지

Brain damage resulting from perinatal cerebral hypoxia and ischemia is a major cause of acute mortality and neurological disabilities, including cerebral palsy (CP) and cognitive dysfunction. In order to establish an experimental hypoxia-ischemia (HI) model of CP for the screening of therapeutics, we operated bilateral common carotid artery ligation (BCAO) and monolateral carotid artery occlusion (MCAO), followed by 15 min of hypoxia (8% oxygen) in 4-day-old rats, and evaluated neurobehavioral disorders. After surgery, the survival rates of male and female BCAO rats were 33.3 and 7.1%, respectively, whereas 100% and 82.4% MCAO rats survived. In neurobehavioral performances, both male and female BCAO rats showed delayed achievement of righting reflex, in contrast to a negligible effect in MACO animals. However, both BCAO and MCAO rats exhibited impairment of cliff avoidance performances, although the physical dysfunction was more severe in BCAO than in MCAO. In global locomotor activity, MCAO rats also displayed decreased fast-moving time comparable BCAO animals, and increased resting and slow-moving times. In addition, MCAO rats showed marked learning and memory deficit in passive avoidance performances, similar to BCAO animals. From immunostaining analyses, severe degradation and loss of myelin basic proteins were observed in the brain of BCAO rats, in contrast to a mild aggregation in MCAO animals. Therefore, it is suggested that MCAO should be a more suitable CP model than BCAO, based on the high survival rate, relatively-mild brain injury, and enough neurobehavioral disorders for the research on preventive and therapeutic compounds.

Effect of L-dopa Medication on Postural Control in Parkinson's Disease: A Posturographic Study

BACKGROUND: The purpose of this study was to investigate abnormalities of postural control in Parkinson's disease (PD) patients during unperturbed stances and externally perturbed stances, and also to assess the effects of L-dopa medication on posture control. METHODS: Thirty PD patients were compared with 30 normal controls. Subjects' spontaneous sway during an unperturbed stance and the postural responses to anterior-posterior tilts of the support surface and of the visual scene were measured by posturography. RESULTS: During the unperturbed stance, displacement, velocity and frequency of the center of foot pressure (COP) were abnormally large in patients OFF treatment. Under L-dopa treatment, the velocity and frequency of COP and axial stiffness of PD patients were reduced, whereas sway amplitude increased. A frequency peak in the COP excursions at 0.7-1.1 Hz, which indicates a resonance behavior of the postural control loop, became reduced under therapy. Abnormal postural responses to tilting of the platform showed that the righting response of the upper body on the lower body was impaired in the PD patients. The postural responses of the PD patients to visual tilt was abnormally exaggerated and not dependent on the stability of the platform unlike the control subjects. These abnormal tilt reactions of the PD patients were resistant to treatment with L-dopa. CONCLUSIONS: These findings suggest that postural instability in PD is more critically related to high sway velocity and frequency than sway amplitude. The patients with PD are short of the ability to use the proprioceptive and visual information for the postural righting response when perturbed.

The Protective Effect of Chlorpromazine on Pentylenetetrazole Induced Seizure

PURPOSE: Chlorpromazine(CPZ) is known to inhibit glutamate dehydrogenase(GDH). Reductive amination of alpha-ketoglutarate is catalyzed by GDH and forms glutamate, a major excitatory neurotransmitter. Thus, we hypothesized that CPZ might have a seizure-protective effect by inhibition of glutamate release from the excitatory presynaptic nerve terminal. The present study was designed to investigate the protective effect of CPZ on pentylenetetrazole(PTZ)-induced seizure in rats. METHODS: Twenty male Sprague-Dawley rats were equally divided into 2 groups. CPZ(20 mg/kg) was administered to experimental animals by subcutaneous injection, while normal saline to control animals. Twenty minutes later, seizures were chemically induced by intraperitoneal injection of PTZ(60 mg/kg). Seizure severity was evaluated by using a scoring system of seizure behaviors:0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater score represents a more severe seizure. RESULTS: The seizure behavior scores(2.8+/-0.2) in the experimental group were significantly lower than those(3.9+/-0.4) in the control group(P<0.05). CONCLUSION: This study demonstrates that CPZ decrease PTZ-induced seizure severity in rats. Our results suggest that CPZ may have a seizure-protective effect. We hope that further studies on this issue should be performed in near future.

The Protective Effect of Chlorpromazine on Pentylenetetrazole Induced Seizure

PURPOSE: Chlorpromazine(CPZ) is known to inhibit glutamate dehydrogenase(GDH). Reductive amination of alpha-ketoglutarate is catalyzed by GDH and forms glutamate, a major excitatory neurotransmitter. Thus, we hypothesized that CPZ might have a seizure-protective effect by inhibition of glutamate release from the excitatory presynaptic nerve terminal. The present study was designed to investigate the protective effect of CPZ on pentylenetetrazole(PTZ)-induced seizure in rats. METHODS: Twenty male Sprague-Dawley rats were equally divided into 2 groups. CPZ(20 mg/kg) was administered to experimental animals by subcutaneous injection, while normal saline to control animals. Twenty minutes later, seizures were chemically induced by intraperitoneal injection of PTZ(60 mg/kg). Seizure severity was evaluated by using a scoring system of seizure behaviors:0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater score represents a more severe seizure. RESULTS: The seizure behavior scores(2.8+/-0.2) in the experimental group were significantly lower than those(3.9+/-0.4) in the control group(P<0.05). CONCLUSION: This study demonstrates that CPZ decrease PTZ-induced seizure severity in rats. Our results suggest that CPZ may have a seizure-protective effect. We hope that further studies on this issue should be performed in near future.

A Study on the Age-Dependent Antiepileptic Effects of the Ketogenic Diet in the Pentylenetetrazole-Seizure Animal Model

PURPOSE: The ketogenic diet(KD) has been felt to be clinically more efficacious at younger ages, presumably because of the enhanced ability of the immature brain to extract and utilize ketone bodies. The present study was designed to investigate age-dependent effects of the KD on pentylenetetrazole(PTZ)-seizure severity in rats. METHODS: A KD([fat]:[protein+carbohydrate] ratio of 4.3:1) was administered to male Sprague-Dawley rats for 3 weeks, while control animals were fed a standard rodent chow. Dietary treatment was initiated at either postnatal 9 or 12 weeks. Seizures were chemically induced by intraperitoneal injection of PTZ(60 mg/kg) and blood beta-hydroxybutyrate (BHB) levels were assayed on treatment day 21. Seizure severity was evaluated by using a scoring system of seizure behaviors:0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater score represents a more severe seizure. RESULTS: In 9 weeks old rats, the mean(+/-SEM) seizure behavior scores were 3.5+/-1.2 [n=19] and 4.4+/-0.9[n=17] for the KD-treated and control groups, respectively(P<0.05), whereas in 12 weeks old animals, no significant differences in seizure behavior scores between the two groups(3.9+/-0.3[n=17] vs. 4.1+/-0.3[n=16], respectively). Blood BHB levels in the KD-treated group were significantly higher than those of the control group in 9 (1.21+/-0.14[n=19] vs. 0.14+/-0.12[n=17] mM, respectively; P<0.001) and 12(0.64+/-0.08[n=17] vs. 0.18+/-0.02[n=16] mM, respectively; P<0.001) weeks old animals. CONCLUSION: The KD was previously reported to decrease PTZ-seizure severity in 3 weeks old rats. In this study, the KD decreases PTZ-seizure severity in 9 weeks old rats, but is ineffective in 12 weeks old rats. These results parallel clinical experience, where the beneficial effects of the KD are felt to be age-dependent.

Effects of the Ketogenic Diet on Pentylenetetrazole-Induced Seizure

PURPOSE: Despite decades of clinical experience with the ketogenic diet(KD), its efficacy and mechanisms of action have been examined in few animal studies. The present study was designed to investigate the effects of the KD on pentylenetetrazole(PTZ)-induced seizure severity in rats. METHODS: Thirty-eight male Sprague-Dawley rats were divided into two equal groups. Dietary treatment was initiated at P22. The KD group was fasted for a day and then fed a KD consisting of a [fat] : [protein+carbohydrate] ratio of 4.3 : 1 for 26 days, while the control group was fed a standard rodent chow. Blood beta-hydroxybutyrate(beta-OHB) levels were assayed on treatment days 0, 20, and 24. Seizures were chemically induced by intraperitoneal injection of PTZ(60mg/kg of body weight) between treatment days 22 and 27. Seizure severity was evaluated by using a scoring system of seizure behaviors : 0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater score represents a more severe seizure. RESULTS: Blood levels of beta-OHB were low(<0.3mM) and showed no significant differences in both groups on day 0. Rats fed the KD developed an increased level of ketosis that was significantly above the levels found in the control group on days 20 and 24 (p<0.001). The KD group(2.37+/-0.27) exhibited significantly(p<0.05) lower seizure score than the control group(3.37+/-0.35). CONCLUSION: The KD was previously reported to increase PTZ-induced seizure thresholds in rats. In our study, rats fed the KD exhibited significantly decreased PTZ-induced seizure scores relative to controls. This suggests that the KD can not only increase the resistance to seizure but also decrease the severity of seizure induced by PTZ.

Unilateral Eyelid Retraction Induced by The Postural Change from Supine to Sitting position

Simultaneous contraction of various muscles with levator palpebrae have been reported as a phenomenon of the paradoxic synkinesis. The authors observed an unilateral eyelid retraction induced by the postural change from supine to sitting position in a 33-month-old girl and a 4-year-old boy. In both cases, the levator function of both eyes was normal and ptosis was not observed. These cases were presumed to be related with postural righting reflex, but the exact neurological basis is not fully defined yet.

Morphologic Studies on Forebrain of Thiamine Deficient Rats Induced by Thiamine eficient Diet and Pyrithiamine

OBJECTIVE: This study was designed for developing a new experimental animal model of Wernicke's encephalopathy, and for investigating the timesequential morphological changes in the thiamine deficient rat brain by thiamine deficient diet with short term treatment of pyrithiamine. METHODS: A total of 40 healthy Sprague-Dawley strain rats, weighing about 2OOgm were used as experimental animals, divided into 10 control rats and 30 thiamine deficient experimental rats. Pyrithiamine (50mg/lOOgm/day) was injected intraperitonially for 9 days and thiamine deficient diet (20gm/rat/day) was continuously supplied until sacrifice. Then thiamine deficient experimental rats were subdivided into 3 groups according'to the exposure time of thiamine deficiency. For observing the morphological features in thalamus, medial mammillary nucleus and CA, sector in hippocampus, luxol-fast blue-cresy violet stain was performed. RESULTS: Treatment with pyrithiamine and thiamine deficient diet results in weight loss and decrement of body temperature on the 12th-14th day, followed by various neurologic manifestations, such as ataxia, hypotonia, circling movement, opisthotonus and loss of righting reflex, on the 16th-20th day, and then died on the 23th-25th, day. Chromatolysis and nuclear condensation of neurons in thalamus, medial mammillary nucleus and CA1 region of hippocampus are observed in group I. Mild edematous changes with neuronal necrosis in group II, and marked neuronal loss with severe edematous necrosis in group III are noted in same regions. CONCLUSION: These time sequential consistent morphological changes suggest that our experimental method could be used as a new animal model of Wernicke's encephalopathy in studying the sequential changes of thiamine deficient rat brain.