Effects of substance P on experimental parkinsonian syndrome

The aim of this study was to investigate the effect of substance P (SP) on parkinsonian syndrome and the generator of pathologically enhanced excitation (GPEE) in the caudate nuclei (CN). Repeated i. p. administration of MPTP in 12 month rats induced oligokinesia and rigidity followed by the high amplitude slow and rapid waves in both CN. The changes of electrical activity in CN were more prominent than in the sensorimotor cortex. The bilateral intracaudate injection of SP (5 micrograms) resulted in an increase in motor activity and almost completely abolished the rigidity. The reduction of extrapyramidal symptoms was considered as a result of the inhibition of GPEE. The changes of the SP balance in nigro-striatal system was suggested to be one of the pathogenetic links of parkinsonian syndrome.     

Effects of intranasally administered substance P in parkinsonian syndrome]

The effect of intranasal substance P injection on parkinsonian syndrome and the generator of pathologically enhanced excitation (GPEE) in caudate nuclei (CN) was investigated. MPTP or reserpine administration in old rats induced oligokinesia, rigidity and tremor followed by the high amplitude slow and rapid waves in both CN. The bilateral intranasal injection of substance P (25 micrograms/kg) resulted in an increase in motor activity and almost completely abolished the rigidity and tremor. The reduction of extrapyramidal symptoms was considered as a result of the inhibition of GPEE in CN. The possibility of substance P entry from nasal cavity into the brain was discussed. The changes of the substance P balance in nigrostriatal system was suggested to be on of the pathogenetic links of parkinsonian syndrome.     

Clinico-electroencephalographic indices of the parkinsonian syndrome induced by MPP+ in rats

The bilateral intranigral injection of 1-methyl-4-phenyl-pyridinium ion (MPP+) (10 g) produced significant oligokinesia, rigidity and weak tremor in rats. The extrapyramidal disturbances manifest a high-amplitude paroxysmal activity (PA) in the structures studied. It was found that the Pa was remarkable and more stable in the caudata nucleus than in other brain structures. It is PA that gives us the real basis to conclude the formation of the generator of pathologically enhanced excitation (GPEE) in the caudata nuclei. The analysis of PA dynamics revealed that the formation of the GPEE in the caudata nuclei correlated with development of parkinsonian syndrome (PS).     

Appearance of parkinsonian syndrome after administration of delta sleep-inducing peptide into the rat substantia nigra

Bilateral microinjection of delta-sleep-inducing peptide (DSIP) (10.0 nmol) into the substantia nigra provoked hypokinesia and rigidity in rats observed during 4.0 hours. Injection of DSIP in dose of 5.0 nmol into the substantia nigra or into the nuclei caudati in dose of 10.0 nmol did not induce such symptoms. The enhanced slow-wave activity was recorded in caudate nuclei during hypokinesia and rigidity which demonstrated the formation of the generator of pathologically enhanced excitation (GPEE). The systemically cyclodol administration resulted in abolishment of rigidity and increase in locomotor activity. The conclusion is that bilateral intranigral DSIP injection caused acute parkinson syndrome in rats due to the formation of cholinergic GPEE in caudate nuclei. The hyperactive caudate nuclei act as the pathologic determinant which induces the parkinson syndrome.     

Parkinson syndrome after administration of acetylcholine into the caudate nuclei

Rats with the Parkinsonian syndrome induced by administration of acetyl choline and proserine into the rostral part of both caudate nuclei manifest an increased electrical activity (EA) in this part. Tremor, oligokinesia and rigidity are characterized by the appearance of paroxysmal EA with high amplitude of slow and rapid waves. The data obtained allow to conclude that neuropathophysiological basis of the Parkinsonian syndrome is the formation of the generator of pathologically enhanced excitation (GPEE) in the caudate nuclei. Some peculiarities of the GPEE activity in tremor and akinetic rigidity syndromes were observed. Intrarostral administration of dopamine or intraperitoneal administration of cyclodol resulted in the inhibition of GPEE and disappearance of clinical manifestations of Parkinsonian syndrome.     

Changes in electric activity of neurons of dorsal raphe nuclei in the development of generator of pathologically enhanced excitation in the nociceptive system

In the experiments on rats it was proved by the method of extracellular registration of impulse neuron activity of dorsal raphe nucleus, that the formation of generator of pathologically enhanced excitation (GPEE) in nociceptive structures of spinal brain underlying the pain syndrome of spinal origin, results in a change of electric neuron activity of dorsal raphe nucleus. These changes are manifested by growing number of background nucleus neurons, the increase of middle frequency of discharges, and assuming pack character of impulse activity. These changes are greater marked in a ventral nucleus part, than in a dorsal one, which is evident of the activation of this antinociceptive system structure. The changes of electric activity of dorsal raphe neurons are stable for a long time after GPEE is formed in nociceptive system, and participate in suppression of GPEE and corresponding pain syndrome.     

Emotional behavior disorders in rats during the formation of a generator of pathologically enhanced excitation in the basomedial nuclei of the amygdaloid complex

Microinjections of kainic acid and ferrous sulfate into basomedial nuclei of both amygdalae resulted in the formation of the generator of pathologically enhanced excitation (GPEE), as evidenced by the epileptical activity (EpA) registered in both nuclei. EpA of different intensity and pattern could be retained for more than three weeks. Hyperactive basomedial nuclei played the role of a primary pathological determinant which caused the complex of emotional and behavioural disorders. Continuous motor depression at the early stages alternated pathologically enhanced activity at the later stages. A number of signs could be considered as the evidence of the affective disorders (motivation suppression, enhanced irritation, anxious excitation). Stereotype behaviour, immobility, rigidity, different types of vegetative disorders (ptosis, constipation, piloerection, loss of weight, respiratory arrhythmia, dystrophic symptoms) were observed in most animals. The emotional, behavioural and vegetative disorders described are compared to the manifestations of the depressive syndrome.     

Modeling of torsion dystonia through electric stimulation of the vermis cerebellum cortex

It was shown in acute experiments on cats that electrical stimulation (ES) (100-300 Hz, 5.0-10.0 V) of cat's cerebellar vermal cortex (lobules V and VI) was followed by head deviation in the direction opposite to that side on which the animal was laying, posture and movement disturbances and also by simultaneously occurred contraction of musculus-antagonists of extremities. The tonic and posture disturbances were observed during 40-60 s after ES cessation. During this time in the zone of ES in cerebellar cortex the high-amplitude synchronized activity was registered which was due to generator of pathologically enhanced excitation (GPEE) formation. Intraperitoneal diazepam (0.5-1.0 mg/kg, 30 min before the observation) pretreatment suppressed GPEE formation that correlated with suppression of syndrome manifestations. The conclusion was made that cerebellar hyperactive cortex, which was due to GPEE induction, might have played the role of pathological hyperactive determinant structure of the described syndrome.     

Effect of the spinal pain syndrome on pain reactions caused by nociceptive thermal stimuli

It has been shown that the reaction of both limbs to thermal pain stimulation was suppressed during spinal pain syndrome development caused by generators of pathologically enhanced excitation (GPEE) formed in the dorsal horns of the spinal cord lumbosacral segments on one side. The analgetic effect on physiological pain was retained long after pain syndrome disappearance (48 hours), the effect was bilateral and was independent of the type of agent producing GPEE. It was shown that neuronal activity in the antinociceptive system key structure (nucleus raphe dorsal) increases. It is assumed that physiological pain relief is caused by enhanced activity in antinociceptive system structures in pain syndrome.     

Dopamine antibodies in the pathogenesis of parkinsonism]

L-DOPA and dopamine (DA) binding antibodies were found in the blood serum of Parkinsonian patients and middle-aged and elderly normal persons. DA-binding serum gamma-globulins of parkinsonian patients injected into rat caudate nuclei induced the pathogenetic mechanism of Parkinson's syndrome (generator of pathologically enhanced excitation) in these brain part and evoked main parkinsonian symptoms (oligokinesia, rigidity, tremor). The serum gamma-globulins of Parkinsonian patients without Da-antibodies caused less pronounced EEG disturbances. Parkinsonian symptoms developed rarely and were shorter and less pronounced compared with the DA-antibody effect. The DA binding antibodies role in Parkinson's syndrome pathogenesis and is L-DOPA therapeutic tolerance formation was discussed.     

Effects of verapamil on behavioral and microcirculatory disorders in pain syndrome of spinal etiology

In the experiments on Wistar rats with pain syndrome of spinal origin (PSSO) caused by the generator of pathologically enhanced excitation (GPEE) in dorsal horns of the spinal cord lumbosacral segments, it was shown that the intravenous verapamil injection (1.25 mg/kg) undoubtedly decreased behaviour response and improves the state of microcirculation. The compound of 10-fold decreased dose does not affect the behaviour response and microcirculation. When PSSO exists, the intravenous injection of analgin (150 mg/kg) produced an effect on the behaviour response and does not produce any action on microcirculation. When verapamil reaches the dorsal surface of the spinal cord (GPEE area) it decreases the behaviour response and microcirculation disorders created in PSSO. The obtained data make it clear that the GPEE depression caused by the verapamil calcium channel blocker weakens PSSO and normalizes the microcirculation.     

Neuro-pathophysiologic effects during primary hyperactivation of the bed nucleus of the stria terminalis in the rat brain

Penicillin administration into the bed nucleus of stria terminalis (BNST) in the rat brain caused epileptiform activity (EpA)--the formation of the generator of pathologically enhanced excitation (GPEE) in the nucleus. GPEE was registered during the first 3 days. EpA was also detected in the amygdala during 5-8 days, and in the hippocamp during the whole period of registration (2-3 weeks). There was the generalized enhancement of synchronized EpA in the range of 6-10 oscillations per s., in some cases with high-amplitude spindle (7-8 oscillations per s.). 50% of animals had emotional behavioural disorders, a marked fear reaction was observed for a month and more. Some animals demonstrated psychotic-like paroxysms with the elements of stereotypy accompanied by high-frequency low-amplitude EpA. It is suggested that when a primary GPEE in BNST is formed, the structures of septo-hippocampal system (BNST, amygdala, hippocamp) play a role of pathological determinants under the influence of which the pathological system consisting of a number of limbic and extrapyramidal structures is formed. Its activity is clinically manifested in the complex polymorphic neuropathological syndrome.     

Duodenal ulcer induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Experiments in rats revealed that the parkinsonian drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in multiple daily doses either per os (p.o.) or subcutaneously (s.c.) induced in a dose-dependent manner solitary or double ("kissing") duodenal ulcers in the rat. MPTP also diminished cerebral concentrations of DOPAC and the duodenal ulcers were prevented by pretreatment with dopamine agonists (e.g., bromocriptine, lergotrile) or monoamine oxidase inhibitors (e.g., pargyline, 1-deprenyl). High doses of MPTP also caused gastric erosions and motility changes resembling parkinsonism (e.g., akinesia, rigidity, forward bending of trunk). This chemical decreased gastric secretion of acid and pepsin, as well as pancreatic bicarbonate, trypsin and amylase. Thus, MPTP causes duodenal ulcers that are possibly associated with impaired defense in the duodenal bulb (e.g., decreased availability of duodenal and pancreatic bicarbonate).     

Signature of Aberrantly Expressed microRNAs in the Striatum of Rotenone-Induced Parkinsonian Rats

Parkinson’s disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P?<?0.05), while miR-7 (0.5 fold, P?<?0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal.     

Effects of activation and lesions of the superior colliculi of the lamina quadrigemina on epileptic activity in rats]

In acute experiments on rats it was shown that activation of SC by bilateral microinjection of penicillin (5-15 IU) or bicuculline (25-50 ng) resulted in the increased latency and decreased severity of i.p. picrotoxin-induced seizures (2 mg/kg). The suppression of behavioral convulsions and the decreased epileptic activity in the hippocampus and cerebral cortex were followed by occurrence of spike discharges in SC with an amplitude of 200-500 mcV and frequency of 5-12/sec which testifies to the formation of penicillin- or bicuculline-induced generator excitation in SC. The lesions of SC by kainic acid administration resulted in the decreased seizure threshold and, also, facilitated the development of seizure under conditions of picrotoxin kindling. The conclusion is made that SC activation plays an important role in the realization of functional integrative activity of the antiepileptic system.     

Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats

The syndrome of cancer cachexia is accompanied by several alterations in lipid metabolism, and the liver is markedly affected. Previous studies showed that moderate exercise training may prevent liver fat accumulation through diminished delivery of lipids to the liver, increased hepatic oxidation and increased incorporation of triacylglycerol (TAG) into very low density lipoprotein (VLDL). Our aim was to examine the influence of moderate intensity training (8 weeks) upon TAG content, VLDL assembly and secretion, apolipoprotein B (apoB) and microsomal transfer protein (MTP) gene expression in the liver of cachectic tumour-bearing rats. Animals were randomly assigned to a sedentary control (SC), sedentary tumour-bearing (ST) or exercise-trained control (EC) or to an exercise trained tumour-bearing (ET) group. Trained rats ran on a treadmill (60% VO(2max)) for 60 min day(-1), 5 day week(-1), for 8 weeks. TAG content and the rate of VLDL secretion (followed for 3 h), as well as mRNA expression of apoB and MTP, and total cholesterol, VLDL-TAG, VLDL-cholesterol, high density lipoprotein cholesterol (HDL-cholesterol) and tumour weight were evaluated. VLDL-cholesterol showed a decrease in ST (p < 0.05) in relation to SC. Serum TAG, VLDL-TAG and tissue TAG content were all increased in ST (p < 0.01), when compared with SC. ST showed a lower rate of VLDL secretion (p < 0.05) and reduced expression of apoB (p < 0.001) and MTP (p < 0.001), when compared with SC. These parameters were restored to control values (p < 0.05) when the animals were submitted to the exercise training protocol. Tumour weight decreased 10-fold after training (p < 0.001). It is possible to affirm, therefore, that endurance training promoted the re-establishment of lipid metabolism in cachectic tumour-bearing animals, especially in relation to VLDL secretion and assembly.     

谷氨酸和MK-801对正常和帕金森模型大鼠纹状体内多巴胺代谢的影响

采用微透析和高效液相色谱一电化学(HPLC-ECD)技术研究了谷氨酸和MK-801对正常和帕金森模型人鼠纹状体内多巴胺代谢的影响。用微透析技术在大鼠纹状体内分别定位给以左旋多巴、L-谷氨酸和／或MK-801,同时收集透析液,用HPLC-ECD方法测定透析液中多巴胺代谢产物的浓度。微透析和HPL-ECD分析结果表明：纹状体内定位给以序旋多巴,正常大鼠和帕金森模型大鼠纹状体内多巴胺代谢产物的浓度均升高;纹状体内定位给以L-谷氨酸,可使正常大鼠纹状体内多巴胺代谢产物的浓度降低,但对帕金森火鼠模型纹状体内多巴胺代谢产物浓度的降低不显著;纹状体内定位给以MK-801,正常人鼠纹状体内多巴胺代谢产物的浓度升高：但对帕金森人鼠模型纹状体内多巴胺代谢产物浓度的升高不显著：纹状体内同时定位给以MK-80l和L-谷氨酸,可以有效防止L-谷氨酸所致正常人鼠纹状体内多巴胺代谢产物浓度的降低。结果提示,谷氦酸可以通过NMDA受体调节多巴胺的代谢。尽管非竞争性NMDA拈抗剂MK-801可以有效防止L-谷氨酸所敛正常人鼠纹状体内多巴胺代谢产物浓度的降低,但却不能有效地改善帕金森大鼠模型纹状体内多巴胺的代谢水平。因此存正常及帕金森病情况下,谷氮酸一多巴胺相互作用机制和MK-801改善帕金森病的机制还有待进一步研究。     

Modelling psychosis in cats by creating a generator of pathologically enhanced excitation in one of the septal nuclei

The experiments on adult freely behaving cats have shown that the injection of penicillin into the internal part (TI) of bed nucleus of stria terminalis (BST) caused the formation of the generator of pathologically enhanced excitation (GPEE). This part of BST became hyperactive and played the role of a pathologic determinant which caused the formation of a complex pathologic system and behavioural disorders with catatonia, stereotypy, food rejection, eating of uneatable things, hypoalgesia, zoosocial behavioural changes, depression of different emotions, etc. The development of these disorders was progressing and was accompanied by corresponding electrophysiological activity in TI and other brain structures studied. Coagulation of GPEE zone at the early stages of the process prevented the development of the above disorders.     

Accumulation of a tumor suppressor p53 protein in rat muscle during a space flight

We previously reported that the space environment consisting of microgravity and space radiation induced an increased level of p53 protein, a tumor suppressor gene product, in rat skin. Here, we report the increase of p53 protein in the muscles of rats that traveled into space. Rats were divided into three groups. The first group remained on earth (VC), and did not show any change in p53 protein level. The second group made a 14-day flight into space on the Second Spacelab Life Science (SLS-2) Mission (F). The third group was experimentally subjected to the same kinds of stress as those in the second group without making a space flight (SC). F and SC rats were sacrificed on day zero (F-0, SC-0) and day nine (F-9, SC-9) after return from space. F-0 rats showed a 1.5-fold increase in p53 protein level compared with that of SC-0 rats, whereas, F-9 rats showed a 1.35-fold increase in p53 protein compared with that of SC-9 rats. These results suggest that the accumulation of cellular p53 protein induced by space environments occurs not only in rat skin cells, but also in rat muscle cells.     

Muscle enzyme adaptations to added load during training and nontraining hours in rats

The effects of added load (20% of body mass) on the selected enzyme activities of red and white quadriceps femoris (QF), soleus, and gastrocnemius muscles of rats were studied. The rats were divided into sedentary control (SC), sedentary control with added load (SC+AL), endurance training (ET), and endurance training with added load (ET+AL) groups (n = 10 rats/group). After 6 wk, the SC+AL group had 57% higher (P less than 0.001) beta-glucuronidase (beta-GU) activity and 24% lower (P less than 0.05) citrate synthase activity in white QF than SC. Citrate synthase activity was also decreased in red QF (P less than 0.05) after the added load was used during nontraining hours. The training with added load induced similar but more pronounced changes than normal endurance training, especially in white QF. The ET+AL group demonstrated higher citrate synthase activity in white QF (P less than 0.001) and gastrocnemius (P less than 0.01) and higher malate dehydrogenase activity (P less than 0.05) and beta-GU activity (P less than 0.001) in white QF than the ET group. ET+AL rats also had higher phosphofructokinase (P less than 0.01) and lower creatine kinase (P less than 0.001) activity in white QF than ET rats. In conclusion, the added load without training had minor adaptive influences on muscles. The added load during training hours seemed to be an effective means of influencing the activation and adaptation in muscles that contain fast glycolytic fibers.