Synaptogenesis and Myopathy Under Acetylcholinesterase Overexpression
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Synaptogenesis
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Cholinesterase
Pyridostigmine Bromide
Agrin
Comparative pyridostigmine kinetics in plasma were measured in 10 healthy subjects given 4 mg iv and 60 mg oral pyridostigmine bromide. As determined from the AUC ratio, oral availability was 11.5% to 18.9% (X̄ = 14.3%). Mean t½ of the plasma level decline after oral dosing was 200 minutes, twice as long as the terminal elimination t½ after intravenous infusion (97 minutes). Thus absorption may proceed at a slower rate than elimination. Comparison of intraindividual data revealed strict dependence of the AUC on the infused dose (2, 4, and 8 mg) in one subject and variability in AUC up to a factor of two when two subjects took oral pyridostigmine three times. Patients with myasthenia who were receiving continuous therapy with oral pyridostigmine had AUC values per unit dose corresponding to those in healthy subjects. Storage stability of pyridostigmine in plasma required acidification of samples and storage at −75° C. When native plasma was kept at −20° C, there was appreciable loss of pyridostigmine within 1 to 2 months, the extent of which depended on the initial concentration. Clinical Pharmacology and Therapeutics (1985) 37, 495–501; doi:10.1038/clpt.1985.78
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Currently, pyridostigmine bromide is an indispensable anticholinesterase agent used worldwide to treat patients with Myasthenia Gravis (MG). However, pyridostigmine bromide was unsuccessful in its "pioneering trials" to treat a series of MG patients. There are important historical landmarks before pyridostigmine bromide becomes useful, safe and indispensable for MG therapy. After 70 years of these "pioneering trials", this article reviews some historical aspects related to them, as well as other preliminary trials using pyridostigmine bromide as therapy for MG patients.
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Abstract : Adult, male rats (300-325 g) were treated with pyridostigmine bromide (n=22) or saline (n=22) to quantitate the effects of severe (64%) cholinesterase inhibition on the ability to work (9.14 m/min, level treadmill) in the heat (35 deg C). Pyridostigmine-treated rats had a mean endurance of 23 min while saline-treated animals ran for nearly 35 min (por=.001). Rates of rectal and skin temperature increments were significantly higher (por=.001) in pyridostigmine-treated rats as were water losses (por=.001). While exercise in the heat to hyperthermic exhaustion effected anticipated increments in circulating urea nitrogen, creatinine, lactate dehydrogenase, and potassium levels, pyridostigmine pretreatment had additive effects on lactate and creatine phosphokinase concentrations. Additionally, pyridostigmine effected a significant (por=.01) hyperglycemia prior to exercise. We concluded that pyridostigmine-induced cholinesterase inhibition had a variety of debilitating effects during work in the heat.
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Plasma levels of pyridostigmine and/or neostigmine were monitored in 8 myasthenic patients who were stabilised on oral pyridostigmine bromide only (60-540 mg per day), and in 9 patients who were stabilised on both neostigmine bromide (15-480 mg per day) and pyridostigmine bromide (240-1080 mg per day), over a period of 12 hr (8.00 a.m. - 8.00 p.m.). Maximum plasma concentrations of pyridostigmine in the first and second groups of patients ranged from 12.4 to 64.5 ng per ml and 15.3 to 144.0 ng per ml respectively. Despite this general intersubject variation in bioavailability of pyridostigmine, there was a direct relationship between the area under plasma concentration-time curves (AUC) and total daily dose in the first group of myasthenic patients (r = 0.95). However, no such observation was noticed neither in all 17 patients nor in the 9 patients who were treated with both drugs. Neostigmine was detected in only one of the second group of patients. It was suggested that neostigmine might interfere with the bioavailability of pyridostigmine when both drugs are concurrently administered orally.
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Background Agrin is a proteoglycan that aggregates nicotinic acetylcholine receptors (AChRs) on neuromuscular junctions and takes part in synaptogenesis in the development of the central nervous system. However, its effects on neural repair and synaptogenesis after stroke are still unclear. Objective This study aimed to investigate the effects of agrin on neural repair and synaptogenesis after stroke and the effects of exercise on this process in vivo and in vitro. Methods Exercise with gradually increased intensity was initiated at 1 day after middle cerebral artery occlusion (MCAO) for a maximum of 14 days. Neurological deficit scores and foot fault tests were used to assess the behavioral recovery. Western blotting, immunofluorescence, and electron microscopic images were used to detect the expression of agrin, synaptogenesis-related proteins, and synaptic density in vivo. In vitro, the ischemic neuron model was established via oxygen-glucose deprivation (OGD). The lentivirus overexpressed agrin and CREB inhibitor were used to investigate the mechanism by which agrin promoted synaptogenesis. Results Exercise promoted behavioral recovery and this beneficial role was linked to the upregulated expression of agrin and increased synaptic density. Overexpressed agrin promoted synaptogenesis in OGD neuron, CREB inhibitor downregulated the expression of agrin and hampered synaptogenesis in cultured neurons. Conclusions These results indicated that exercise poststroke improved the recovery of behavioral function after stroke. Synaptogenesis was an important and beneficial factor, and agrin played a critical role in this process and could be a potential therapeutic target for the treatment of stroke and other nervous system diseases.
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ABSTRACT Agrin, a 200 kDa extracellular matrix protein, participates in the maturation of the postsynaptic target at the neuromuscular junction. Although agrin has also been detected in central neurons, little is known about its role in the formation of their synapses. In the present study, the pattern of expression, localization and function of agrin in developing hippocampal neurons were analyzed. The results indicate that an increase in agrin protein levels precedes synaptogenesis in cultured hippocampal neurons. This increase in agrin expression is accompanied by its extracellular deposition along the distal third of the axon. To investigate whether agrin plays a role during synapse formation, its expression in cultured hippocampal neurons was suppressed by means of antisense oligonucleotide treatment. The suppression of agrin expression results in the impairment of dendritic development and the formation of fewer synapses than in non-treated or sense-treated neurons. Moreover, this decreased synaptic density is accompanied by a selective inhibition of the clustering of GABA receptors. These results lead to the conclusion that agrin may be an important regulator of the maturation of dendrites and synaptogenesis in central neurons.
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Agrin controls the formation of the neuromuscular junction. Whether it regulates the differentiation of other types of synapses remains unclear. Therefore, we have studied the role of agrin in cultured hippocampal neurons. Synaptogenesis was severely compromised when agrin expression or function was suppressed by antisense oligonucleotides and specific antibodies. The effects of antisense oligonucleotides were found to be highly specific because they were reversed by adding recombinant agrin and could not be detected in cultures from agrin-deficient animals. Interestingly, the few synapses formed in reduced agrin conditions displayed diminished vesicular turnover, despite a normal appearance at the EM level. Thus, our results demonstrate the necessity of agrin for synaptogenesis in hippocampal neurons.
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Abstract Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. A 12 years old female patient diagnosed with myasthenia gravis was consulted to our clinic with the complaint of urticaria due to pyridostigmine bromide. The oral challenge test performed with pyridostigmine bromide was positive. As the patient was required to be administered with pyridostigmine bromide and due to lack of any alternatives, administration of the desensitization was decided. During and after the desensitization protocol, no reaction was observed. In this presentation, a successful desensitization protocol for pyridostigmine bromide in a child with myasthenia gravis patient was discussed.
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Abstract The subacute effects of pyridostigmine bromide were investigated on the contractile properties of rat extensor digitorum longus (EDL) and diaphragm muscles. The cholinesterase inhibitor was delivered via subcutaneously implanted osmotic minipumps (Alzet®) at 9 μg h −1 (low dose) or 60 μg h −1 (high dose). Animals receiving high‐dose pyridostigmine pumps exhibited marked alterations in muscle properties within the first day of exposure that persisted for the remaining 13 days. With 0.1 Hz stimulation, EDL twitch tensions of treated animals were elevated relative to control. Repetitive stimulation at frequencies >1 Hz led a use‐dependent depression in the amplitude of successive twitches during the train. Recovery from pyridostigmine was essentially complete by 1 day of withdrawal. Rats implanted with low‐dose pyridostigmine pumps showed little or no alteration of in vivo twitch tensions during the entire 14 days of treatment. Diaphragm and EDL muscles excised from pyridostigmine‐treated rats and tested in vitro showed no significant alterations in twitch and tetanic tensions and displayed the same sensitivity as muscles of control animals to subsequent pyridostigmine exposures. In the presence of atropine, subacutely administered pyridostigmine protected rats from two LD 50 doses of the irreversible cholinesterase inhibitor, soman. In the absence of atropine, the LD 50 of soman was not altered by subacute pyridostigmine treatment.
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