Cerebral hypoxia-ischemia in immature rats: involvement of mitochondrial permeability transition?

The aim of this study was to evaluate the involvement of mitochondrial membrane permeability transition (MPT) after hypoxia-ischemia (HI) in 7-day-old rats. [14C]2-deoxyglucose (DOG) was administered to controls, and at various time points after HI. MPT in the cerebral cortex was measured as entrapment of DOG-6-P in mitochondria. Another group of rats was treated with the MPT inhibitor cyclosporin A (CsA; 10-50 mg/kg i.p.) or vehicle before and after HI, and the effect on brain injury and mitochondrial respiration was evaluated. A significant increase in DOG-6-P entrapment in mitochondria indicated that MPT occurred in two phases: a primary MPT after 0-1.5 h and a secondary MPT after 6.5-8 h of reperfusion. However, CsA did not affect brain injury or mitochondrial respiration. The data suggest that MPT occurred after HI but does not provide evidence for its involvement in the development of injury.     

Does abnormal branching of inputs to motor neurones explain abnormal muscle cocontraction in cerebral palsy?

The common synaptic drive shared between two groups of motor neurones synchronizes the timing of discharges between the motor-neurone groups. Recordings were made of motor-unit discharges during cocontraction of ipsilateral pairs of thumb muscles in eight subjects with cerebral palsy (CP) aged 4 to 13 years and eight neurologically healthy subjects aged 4 to 12 years, and in pairs of lower-limb muscles in 21 subjects with CP and 21 control subjects, both aged 3 to 15 years. Common synaptic drive, likely to be derived at least partly from activity in branched corticospinal-tract neurones, produced motor-unit synchronization between pairs of thumb muscles in control subjects but was absent in all subjects with CP. Motor unit synchronization was not found between lower-limb antagonist muscles that cocontract abnormally in CP, nor was synchronization present in more widely separated muscle pairs. Therefore, abnormal patterns of muscle activation and more widespread muscle reflex responses do not result from an abnormal distribution of common synaptic drive in CP.     

Autosomal dominant congenital spinal muscular atrophy--a possible developmental deficiency of motor neurones?

We describe a kindred with an unusual congenital lower motor neuron disorder with significant but static muscle weakness predominantly affecting the lower limbs. The proband had talipes equinovarus and congenital hip contractures and did not walk until 19 months of age. Lower-extremity predominant, primarily proximal weakness was identified on assessment at three years. Over a 20 year follow-up there has been no clinical progression. The proband has a four-year-old daughter with very similar clinical findings. Electromyography and muscle biopsy suggest reduced numbers of giant normal duration motor units with little evidence of denervation or reinnervation. Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described. It is possible that the disorder is due to a congenital deficiency of motor neurons.     

Protective effect of sodium valproate on motor neurons in the spinal cord following sciatic nerve injury in rats

BACKGROUND: Sodium valproate (VPA) is used to be an effective anti-epileptic drug. VPA possesses the characteristics of penetrating rapidly through the blood-brain barrier (BBB) and increasing levels of Bcl-2 and growth cone-associated protein (GAP) 43 in spinal cord. OBJECTIVE: To observe the effect of VPA on Bcl-2 expression and motor neuronal apoptosis in spinal cord of rats following sciatic nerve transection. DESIGN: Randomized controlled experiment. SETTING: Department of Hand Surgery and Microsurgery, Wuhan Puai Hospital. MATERIALS: A total of 30 male healthy SD rats of clean grade and with the body mass of 180-220 g were provided by Experimental Animal Center of Medical College of Wuhan University. Sodium Valproate Tablets were purchases from Hengrui Pharmaceutical Factory, Jiangsu. METHODS: The experiment was performed in the Central Laboratory of Wuhan Puai Hospital and Medical College of Wuhan University from February to May 2006. Totally 30 rats were randomly divided into two groups: treatment group (n =15) and model group (n =15). Longitudinal incision along backside of right hind limbs of rats was made to expose sciatic nerves, which were sharply transected 1 cm distal to the inferior margin of piriform muscle after nerve liberation under operation microscope to establish sciatic nerve injury rat models. Sodium Valproate Tablets were pulverized and diluted into 50 g/L suspension with saline. On the day of operation, the rats in the treatment group received 6 mL/kg VPA suspension by gastric perfusion, once a day, whereas model group received 10 mL/kg saline by gastric perfusion, once a day. L4-6 spinal cords were obtained at days 1, 4, 7, 14 and 28 after operation, respectively. Terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique and immunohistochemical method (SP method) were used to detect absorbance (A) of neurons with positive Bcl-2 expression. Apoptotic rate of cells (number of apoptotic cells/total number of cells×100%) was calculated. MAIN OUTCOME MEASURES: A value of neurons with positive Bcl-2 expression and apoptotic rate in spinal cord of rats in the two groups. RESULTS: A total of 30 SD rats were involved in the result analysis. ①expression of positive Bcl-2 neurons: A value of positive Bcl-2 neurons were 0.71±0.02, 0.86±0.04, 1.02±0.06 at days 4, 7 and 14, respectively after operation in the treatment group, which were obviously higher than those in the model group (0.62±0.03, 0.71±0.05, 0.89±0.04, t = 3.10-4.50, P < 0.05). ②apoptotic result of motor neurons: Apoptotic rate of motor neurons in spinal cord was (6.91±0.89)% and (15.12±2.34)% at days 7 and 14 in the treatment group, which was significantly lower than those in the model group [(9.45±1.61)%, (19.35±0.92)%, t = 2.39, 3.03. P < 0.05]. CONCLUSION: VPA can increase expression of Bcl-2 in spinal cord and reduce neuronal apoptosis in rats following sciatic nerve injury, and has protective effect on motor neuron in spinal cord of rats.     

Long-Evans rats have a larger cortical topographic representation of movement than Fischer-344 rats: a microstimulation study of motor cortex in naïve and skilled reaching-trained rats

Intracortical microstimulation of the frontal cortex evokes movements in the contralateral limbs, paws, and digits of placental mammals including the laboratory rat. The topographic representation of movement in the rat consists of a rostral forelimb area (RFA), a caudal forelimb area (CFA), and a hind limb area (HLA). The size of these representations can vary between individual animals and the proportional representation of the body parts within regions can also change as a function of experience. To date, there have been no investigations of strain differences in the cortical map of rats, and this was the objective of the present investigation. The effect of cortical stimulation was compared in young male Long-Evans rats and Fischer-344 rats. The overall size of the motor cortex representation was greater in Long-Evans rats compared to Fischer-344 rats and the threshold required to elicit a movement was higher in the Fischer-344 rats. An additional set of animals were trained in a skilled reaching task to rule out the possibility that experiential differences in the groups could account for the result and to examine the relationship between the differences in topography of cortical movement representations and motor performance. The Long-Evans rats were quantitatively and qualitatively better in skilled reaching than the Fischer-344 rats. Also, Long-Evans rats exhibited a relatively larger area of the topographic representation and lower thresholds for eliciting movement in the contralateral forelimb. This is the first study to describe pronounced strain-related differences in the microstimulation-topographic map of the motor cortex. The results are discussed in relation to using strain differences as a way of examining the behavioral, the physiological, and the anatomical organization of the motor system.     

Effects of acrous gramineus and its component, alpha-asarone, on apoptosis of hippocampal neurons after seizure in immature rats**☆

BACKGROUND： α-asarone and acrous gramineus have been shown to play a necessary function in enhancing the reactivity and convulsant threshold to electric stimulation of immature rats. They have also been shown to effectively suppress epileptic seizures induced by pentylenetetrazol in young rats. However, the mechanisms for these roles have been still unclear. OBJECTIVE： To observe the effects in immature rats of acrous gramineus and α -asarone on apoptosis of hippocampal neurons after epileptic seizure at the protein level, and to analyze the mechanism for these effects. DESIGN： A randomized controlled animal experiment. SETTINGS： Department of Pediatrics, First Hospital of Jilin University; Department of Histology and Embryology, Norman Bethune Medical School of Jilin University; Department of Internal Medicine, Children＇s Hospital of Changchun City; Department of Neurology, First Clinical Hospital affiliated to Harbin Medical University. MATERIALS： Fifty 3-week old Wistar rats, 34-40 g, irrespective of gender, were provided by Gaoxin Research Center of Medical Animal Experiment, Changchun. The animals were treated according to the animal ethical standards. The following chemicals were used for this study： acrous gramineus powders or infusion （Batch No, 0307113, Tianjiang Medicine Company Limited, Jiangyin）, α-asarone tablets （Batch No. 030219, Tianwei Pharmaceutical Factory, Shenyang）, and phenobarbital sodium tablets （Batch No. 020608, Xinya Medicine Company Limited, Shanghai）. The animals were divided into five groups randomly. First, ten rats were chosen as the normal controls. The remaining rats were treated with i.p. injections of pentylenetetrazol to stimulate an epileptic model. METHODS： The experiments were performed at the Neurological Laboratory of the First Hospital of Jilin University between October and December 2004. The rats were treated with i.p. injections of pentylenetetrazol （60 mg/kg） to establish an epileptic model. According to Racine＇ s standard, animal     

L-alpha-aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra-nigral lipopolysaccharide (LPS)-induced experimental Parkinsonism in male Wistar rats via simultaneous co-injection of the astrocytic toxin L-alpha-aminoadipic acid (L-AAA). Simultaneous intra-nigral injection of L-AAA attenuated the LPS-induced loss of tyrosine hydroxylase-positive (TH⁺) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH⁺ dopaminergic nerve terminals in the striatum. L-AAA also repressed LPS-induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L-AAA abrogated intra-nigral LPS-induced glial fibrillary acidic protein-positive (GFAP⁺) reactive astrogliosis and attenuated the LPS-mediated increases in nigral S100β expression levels in a time-dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1-positive (Iba1⁺) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.     

The involvement of serotonin and sex hormones in the generation of “killer rats”

An aggressive social environment induces chronic stress, pathological aggression, and the generation of killer rats. During natural or pilocarpine-induced aggression, serotonin content decreases by more than 50%. Aggression also correlates with quantitative alterations in the contents of male sex hormones. Specifically, castration of animals results in a significant attenuation of aggression, whereas injection of the male sex hormone testosterone leads to stimulation of aggressive behavior in rats. Rats that are tired after swimming in a pool exhibited substantially lower aggression. We can conclude that in order to avoid aggressive behavior in teenagers, physical activity should be included in intervals between lessons for neutralization of hormones and other biologically active agents that are directly related to formation of aggressive behavior.     

Repeated febrile convulsions impair hippocampal neurons and cause synaptic damage in immature rats： neuroprotective effect of fructose-1,6-diphosphate

Fructose-1,6-diphosphate is a metabolic intermediate that promotes cell metabolism. We hypothesize that fructose-1,6-diphosphate can protect against neuronal damage induced by febrile convulsions. Hot-water bathing was used to establish a repetitive febrile convulsion model in rats aged 21 days, equivalent to 3–5 years in humans. Ninety minutes before each seizure induction, rats received an intraperitoneal injection of low- or high-dose fructose-1,6-diphosphate(500 or 1,000 mg/kg, respectively). Low- and high-dose fructose-1,6-diphosphate prolonged the latency and shortened the duration of seizures. Furthermore, high-dose fructose-1,6-diphosphate effectively reduced seizure severity. Transmission electron microscopy revealed that 24 hours after the last seizure, high-dose fructose-1,6-diphosphate reduced mitochondrial swelling, rough endoplasmic reticulum degranulation, Golgi dilation and synaptic cleft size, and increased synaptic active zone length, postsynaptic density thickness, and synaptic interface curvature in the hippocampal CA1 area. The present findings suggest that fructose-1,6-diphosphate is a neuroprotectant against hippocampal neuron and synapse damage induced by repeated febrile convulsion in immature rats.     

Effects of (−)-OSU6162 and ACR16 on motor activity in rats,indicating a unique mechanism of dopaminergic stabilization

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.     

Entrapment of motor nerves in motor neuron disease: does double crush occur?

OBJECTIVE: To investigate whether "diseased nerves" are more prone to entrapment neuropathy than normal nerves. Nerve conduction studies of human neuropathies have shown that electrophysiological abnormalities are often most prominent at potential sites of nerve entrapment, and entrapments are more common in patients with radiculopathies--a concept designated as "double crush". As entrapment neuropathies commonly occur in otherwise healthy subjects, it is unclear whether this relation is coincidental or whether peripheral nerves affected by disease are rendered more susceptible to effects of repeated minor trauma, traction, or mechanical compression. METHODS: Sequential ulnar nerve conduction studies were prospectively performed at baseline and at four, eight, and 12 month intervals in 16 patients with amyotrophic lateral sclerosis. Ulnar nerve entrapment was defined as a focal reduction (> 10 m/s) in conduction velocity in the across-elbow segment. RESULTS: Ulnar sensory and motor nerve fibres showed similar findings of ulnar nerve entrapment at baseline and at follow up over the period of the study. Nerves with ulnar nerve entrapment showed a significantly greater reduction in distal motor amplitudes than nerves without entrapment, even though distal ulnar sensory amplitudes remained unchanged. CONCLUSIONS: Motor nerves in motor neuron disease do not seem to be more susceptible to entrapment at the elbow than do healthy sensory nerves, thus casting doubt on the double crush hypothesis. Nerves with double pathology (amyotrophic lateral sclerosis and ulnar nerve entrapment), however, seem to undergo more rapid axonal loss than do nerves with single pathology (amyotrophic lateral sclerosis or ulnar nerve entrapment alone).     

Standard neurophysiological studies and motor evoked potentials in evaluation of traumatic brachial plexus injuries – A brief review of the literature

Purpose

Traumatic damage to the brachial plexus is associated with temporary or permanent motor and sensory dysfunction of the upper extremity. It may lead to the severe disability of the patient, often excluded from the daily life activity. The pathomechanism of brachial plexus injury usually results from damage detected in structures taking origin in the rupture, stretching or cervical roots avulsion from the spinal cord. Often the complexity of traumatic brachial plexus injury requires a multidisciplinary diagnostic process including clinical evaluation supplemented with clinical neurophysiology methods assessing the functional state of its structures. Their presentation is the primary goal of this paper.

Progression of motor symptoms in Parkinson’s disease

Parkinson’s disease(PD)is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms-rigidity,bradykinesia and tremor-due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms.However,the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.     

Experimental studies of pedunculopontine functions: are they motor, sensory or integrative?

The pedunculopontine tegmental nucleus (PPTg) is involved in Parkinson's disease and has become a therapeutic target. However, its normal functions are uncertain: are they motor, sensory or integrative? This position paper reviews PPTg structure and considers experiments designed to understand its behavioural functions. The PPTg is part of the corticostriatal architecture and, consistent with this, a core deficit following lesion is the inability to properly establish action-outcome associations. Understanding normal PPTg structure and function will provide insight into the role it has in Parkinson's disease and related disorders, and will benefit the development of surgical treatments aimed here.     

“How to do things with Words”: Role of motor cortex in semantic representation of action words

Language, believed to have originated from actions, not only functions as a medium to access other minds, but it also helps us commit actions and enriches our social life. This fMRI study investigated the semantic and neural representations of actions and mental states. We focused mainly on language semantics (comprehending sentences with action words versus those with mental state words). While in an fMRI scanner, twenty-four healthy, right-handed adult volunteers read a series of sentences with a verb depicting either a mental state (e.g., deceive, persuade) or an action (e.g., punch, kick), and answered a comprehension question that followed. Overall, this task showed brain activation in the left inferior frontal gyrus and in the left posterior superior temporal sulci. While comprehending sentences with mental state terms, participants showed greater activation in left orbitofrontal, and in left precuneus areas. On the other hand, the action sentences recruited more primary motor, left inferior parietal, bilateral occipital, right superior temporal, and right inferior frontal areas. The findings of this study underscore the role of motor and visuospatial involvement in action word representation in the human brain.     

“A” motor neuron disease

Importance:Allgrove syndrome is a rare autosomal recessive disorder characterised by achalasia, alacrima, adrenal insufficiency, autonomic dysfunction and amyotrophy. The syndrome has been described in childhood and adult presentation, as in our case, is very rare. There is a considerable delay in diagnosis due to lack of awareness about the syndrome.Observations:We report a single case of a 36 year old man who was initially diagnosed and treated for achalasia cardia in our institute 14 years before. After 8 years he presented again with weakness and wasting predominantly distally. He had tongue fasciculations, brisk reflexes and extensor plantar. After supportive electrophysiological studies he was diagnosed as Amyotrophic lateral sclerosis. After 5 years he presented with generalised fatigue without any significant worsening of his neurological status. On reevaluation he had alacrimia, autonomic dysfunction and mild ACTH resistance.Conclusions and relevance:Allgrove syndrome may be an underdiagnosed cause of multisystem neurological disease due to the heterogeneous clinical presentation as well as for ignorance of clinician about the syndrome. Based on our case, we also believe that there does exist a subgroup of patients who follow a less severe and chronic course. Recognition of syndrome allows for treatment of autonomic dysfunction, adrenal insufficiency and dysphagia.     

Timed tests of motor function in Parkinson’s disease

IntroductionTimed tests of motor function in Parkinson’s disease (PD) may be useful for the diagnosis of bradykinesia or to monitor disease progression or treatment response. However, normal ranges have not been established.AimTo define normal ranges of hand-tapping and timed walking tests in non-parkinsonian controls and compare with PD patients’ performance.MethodsWe recruited PD patients and age- and gender-matched controls for a prospective community-based incidence study of parkinsonian disorders in North-East Scotland. We counted the times participants tapped between two counters in 30 s. We also timed a 6m get-up-and-go test. We assessed age and gender effects and calculated 95% reference ranges for controls. We compared PD patients with controls.ResultsWe recruited 157 controls and 138 newly diagnosed, untreated PD patients (mean ages 75 and 73). The 95% control reference range for tapping scores with the dominant hand was 18–74 taps. Males and younger participants performed significantly better. PD patients performed less well (mean difference 15 taps, p < 0.001) but only 10% had tapping scores below the control range. The 95% control reference range for the get-up-and-go test was 9–27 s. Walking times increased significantly with age, but gender had no effect. PD patients were slower (median difference 4.5s, p < 0.001) but only 17% were slower than the control range.DiscussionAlthough PD patients performed more slowly than matched controls, timed tests were not helpful diagnostically because few incident patients were outside the normal reference ranges. Further work is needed on their utility in monitoring disease progression.