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Molecules (Basel, Switzerland) Jun 2021Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by...
Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by the reduction of Weinreb amides and a single-step attachment of a 1-methyl-imidazole residue allowed for the concise synthesis of both enantiomers of pilocarpine.
Topics: 4-Butyrolactone; Amides; Carboxylic Acids; Esterification; Furans; Hydrogenation; Hydrolysis; Pilocarpine; Stereoisomerism
PubMed: 34208623
DOI: 10.3390/molecules26123676 -
Neuropharmacology Jun 2021Status epilepticus (SE) is a medical emergency with continuous seizure activity that causes profound neuronal damage, morbidity, or death. SE incidents can arise...
Status epilepticus (SE) is a medical emergency with continuous seizure activity that causes profound neuronal damage, morbidity, or death. SE incidents can arise spontaneously but mostly are elicited by seizurogenic triggers. Chemoconvulsants such as the muscarinic agonist pilocarpine and, organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and, the nerve agent soman, can induce SE. Pilocarpine, DFP, and soman share a common feature of cholinergic crisis that transitions into a state of refractory SE, but their comparative profiles remain unclear. Here, we evaluated the comparative convulsant profile of pilocarpine, DFP, and soman to produce refractory SE and brain damage in rats. Behavioral and electrographic seizures were monitored for 24 h after exposure, and the extent of brain injury was determined by histological markers of neuronal injury and degeneration. Seizures were elicited rather slowly after pilocarpine as compared to DFP or soman, which caused rapid onset of spiking that swiftly developed into persistent SE. Time-course of SE activity after DFP was comparable to that after soman, a potent nerve agent. Diazepam controlled pilocarpine-induced SE, but it was ineffective in reducing OP-induced SE. All three agents produced modestly different degrees of neuronal injury and neurodegeneration in the brain. These results reveal distinct convulsant and neuronal injury patterns following exposure to cholinergic agonists, OP pesticides, and nerve agents. A battery of SE models, especially SE induced by cholinergic agents and other etiologies including epilepsy and brain tumors, is essential to identify novel anticonvulsant therapies for the management of refractory SE.
Topics: Animals; Anticonvulsants; Brain; Brain Injuries; Diazepam; Hippocampus; Isoflurophate; Male; Neurons; Organophosphates; Pilocarpine; Rats; Rats, Sprague-Dawley; Soman; Status Epilepticus
PubMed: 33878303
DOI: 10.1016/j.neuropharm.2021.108571 -
Experimental Eye Research May 2010Many studies have used pilocarpine to stimulate accommodation in both humans and monkeys. However, the concentrations of pilocarpine used and the methods of...
Many studies have used pilocarpine to stimulate accommodation in both humans and monkeys. However, the concentrations of pilocarpine used and the methods of administration vary. In this study, three different methods of pilocarpine administration are evaluated for their effectiveness in stimulating accommodation in rhesus monkeys. Experiments were performed in 17 iridectomized, anesthetized rhesus monkeys aged 4-16 years. Maximum accommodation was stimulated in all these monkeys with a 2% pilocarpine solution maintained on the cornea for at least 30 min in a specially designed perfusion lens. In subsequent topical pilocarpine experiments, baseline refraction was measured with a Hartinger coincidence refractometer and then while the monkeys were upright and facing forward, commercially available pilocarpine (2, 4, or 6%) was applied topically to the cornea as 2 or 4 drops in two applications or 6 drops in three applications over a five minute period with the eyelids closed between applications. Alternatively, while supine, 10-12 drops of pilocarpine were maintained on the cornea in a scleral cup for 5 min. Refraction measurements were begun 5 min after the second application of pilocarpine and continued for at least 30 min after initial administration until no further change in refraction occurred. In intravenous experiments, pilocarpine was given either as boluses ranging from 0.1mg/kg to 2mg/kg or boluses followed by a constant infusion at rates between 3.06 mg/kg/h and 11.6 mg/kg/h. Constant 2% pilocarpine solution on the eye in the perfusion lens produced 10.88+/-2.73 D (mean+/-SD) of accommodation. Topically applied pilocarpine produced 3.81 D+/-2.41, 5.49 D+/-4.08, and 5.55 D+/-3.27 using 2%, 4%, and 6% solutions respectively. When expressed as a percentage of the accommodative response amplitude obtained in the same monkey with constant 2% pilocarpine solution on the eye, the responses were 34.7% for 2% pilocarpine, 48.4% for 4% pilocarpine, and 44.6% for 6% pilocarpine. Topical 4% and 6% pilocarpine achieved similar, variable accommodative responses, but neither achieved maximum accommodation. IV boluses of pilocarpine achieved near maximal levels of accommodation at least ten times faster than topical methods. Doses effective for producing maximum accommodation ranged from 0.25mg/kg to 1.0mg/kg. IV pilocarpine boluses caused an anterior movement of the anterior lens surface, a posterior movement of the posterior lens surface, and a slight net anterior movement of the entire lens. Considerable variability in response amplitude occurred and maximum accommodative amplitude was rarely achieved with topical application of a variety of concentrations of commercially available pilocarpine. Intravenous infusion of pilocarpine was a rapid and reliable method of producing a nearly maximal accommodative response and maintaining accommodation when desired.
Topics: Accommodation, Ocular; Administration, Topical; Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Infusions, Intravenous; Injections, Intravenous; Iridectomy; Macaca mulatta; Muscarinic Agonists; Pilocarpine; Propofol; Refraction, Ocular
PubMed: 20159011
DOI: 10.1016/j.exer.2010.02.005 -
ENeuro 2019is moving forward with a new initiative asking authors to present their results with estimation statistics and not to rely solely on values. In this editorial, I would...
is moving forward with a new initiative asking authors to present their results with estimation statistics and not to rely solely on values. In this editorial, I would like to introduce to you the concept of this new statistics while first discussing my evaluation of the present situation and my own experience with using statistics to interpret results, then I will propose a solution and how we will move forward in the journal. I have also included my own experience using these new statistics and provided a list of resources. This new initiative will not change what is already acceptable for statistics in the journal; it is to encourage a simple addition of using estimation statistics.
Topics: Animals; Cognition; Epilepsy; Housing; Mice; Pilocarpine; Rats; Seizures
PubMed: 31453315
DOI: 10.1523/ENEURO.0259-19.2019 -
The British Journal of Ophthalmology Aug 1977During the course of negative provocative test for closed-angle glaucoma using pilocarpine and phenylephrine 60% of eyes develop significant reductions in outflow...
During the course of negative provocative test for closed-angle glaucoma using pilocarpine and phenylephrine 60% of eyes develop significant reductions in outflow facility at some stage during the test. It is shown that these reductions can be explained by postulating the presence of partial-angle closure since: (1) A random sample (6) of 53 eyes showing an abnormal response subsequently had a peripheral iridectomy. On reprovoking they then behaved as normal eyes with a uniform increase in outflow. (2) Fifty-eight eyes that had a peripheral iridectomy for closed-angle glaucoma (spontaneous or induced) responded to provocative testing as do normal eyes.
Topics: Drug Combinations; Glaucoma; Humans; Intraocular Pressure; Iris; Phenylephrine; Pilocarpine
PubMed: 911732
DOI: 10.1136/bjo.61.8.525 -
JCI Insight Jan 2024Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of...
Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.
Topics: Animals; Nestin; Pilocarpine; Seizures; Status Epilepticus; Hippocampus; Neurogenesis; Epilepsy
PubMed: 38193536
DOI: 10.1172/jci.insight.175627 -
International Journal of Molecular... Oct 2023Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is...
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Topics: Rats; Animals; Epilepsy, Temporal Lobe; Pilocarpine; Lamotrigine; Lithium; Interleukin 1 Receptor Antagonist Protein; Anticonvulsants; Seizures; Hippocampus; Disease Models, Animal
PubMed: 37895080
DOI: 10.3390/ijms242015400 -
Current Neuropharmacology 2018Choline alfoscerate (α-GPC) and Cytidine 5'-diphosphocholine (CDPCholine) are both acetylcholine precursors and are considered to act as pro-cholinergic nootropic... (Review)
Review
BACKGROUND
Choline alfoscerate (α-GPC) and Cytidine 5'-diphosphocholine (CDPCholine) are both acetylcholine precursors and are considered to act as pro-cholinergic nootropic agents. Acetylcholine precursors have also recently found frequent use in the neurology clinic. Stroke and many types of dementia have been shown to respond favorably after treatment with these agents, not only in terms of cognitive dysfunction but also behavioral and psychological symptoms. The primary mechanisms of Acetylcholine precursors are the following: 1) Acetylcholine precursors themselves are used in the biosynthesis of acetylcholine and 2) byproducts like glycerophosphate have protective functions for neuronal phospholipids. However, whether acetylcholine precursors have a similar effect in treating cognitive impairment in patients with epilepsy remains controversial.
METHODS
Our previous studies investigating acetylcholine precursors in seizure-experienced animals have produced variable results that were dependent on the timing of administration.
RESULTS
Early administration of CDP-choline immediately after seizure increased neuronal death, blood-brain barrier (BBB) disruption and microglial activation in the hippocampus. However, administration of α-GPC starting 3 weeks after seizure (late administration) improved cognitive function through reduced neuronal death and BBB disruption, and increased neurogenesis in the hippocampus.
CONCLUSION
These seemingly contradictory results may be attributed to both epileptogenic features and neuroprotective functions of several acetylcholine precursors.
Topics: Animals; Cell Death; Cytidine Diphosphate Choline; Glycerylphosphorylcholine; Muscarinic Agonists; Neurons; Pilocarpine; Seizures
PubMed: 28521701
DOI: 10.2174/1570159X15666170518150053 -
International Journal of Pharmaceutics Apr 2018Radiotherapy is a life-saving treatment for head and neck cancers, but almost 100% of patients develop dry mouth (xerostomia) because of radiation-induced damage to... (Review)
Review
Radiotherapy is a life-saving treatment for head and neck cancers, but almost 100% of patients develop dry mouth (xerostomia) because of radiation-induced damage to their salivary glands. Patients with xerostomia suffer symptoms that severely affect their health as well as physical, social and emotional aspects of their life. The current management of xerostomia is the application of saliva substitutes or systemic delivery of saliva-stimulating cholinergic agents, including pilocarpine, cevimeline or bethanechol tablets. It is almost impossible for substitutes to replicate all the functional and sensory facets of natural saliva. Salivary stimulants are a better treatment option than saliva substitutes as the former induce the secretion of natural saliva from undamaged glands; typically, these are the minor salivary glands. However, patients taking cholinergic agents systemically experience pharmacology-related side effects including sweating, excessive lacrimation and gastrointestinal tract distresses. Local delivery direct to the buccal mucosa has the potential to provide rapid onset of drug action, i.e. activation of minor salivary glands within the buccal mucosa, while sparing systemic drug exposure and off-target effects. This critical review of the technologies for the local delivery of saliva-stimulating agents includes oral disintegrating tablets (ODTs), oral disintegrating films, medicated chewing gums and implantable drug delivery devices. Our analysis makes a strong case for the development of ODTs for the buccal delivery of cholinergic agents: these must be patient-friendly delivery platforms with variable loading capacities that release the drug rapidly in fluid volumes typical of residual saliva in xerostomia (0.05-0.1 mL).
Topics: Drug Delivery Systems; Head and Neck Neoplasms; Humans; Mouth Mucosa; Muscarinic Agonists; Pilocarpine; Quinuclidines; Radiation Injuries; Saliva; Thiophenes; Time Factors; Xerostomia
PubMed: 29425763
DOI: 10.1016/j.ijpharm.2018.02.004 -
Brain Research Bulletin Sep 2018Ascorbic acid (AA) administration has been associated with neuroprotection against oxidative stress, although at high doses it can facilitate oxidation and acts like a...
Ascorbic acid (AA) administration has been associated with neuroprotection against oxidative stress, although at high doses it can facilitate oxidation and acts like a proconvulsing drug. The pilocarpine-induced epilepsy model has been widely studied. However, less is known about the effects of sub-convulsive doses of pilocarpine on brain activity in immature animals under normal or deficient nutritional conditions. Herein, we investigated the effects of chronic pilocarpine administration in a sub-convulsive dose, with or without AA, on the excitability-related phenomenon denominated as cortical spreading depression (CSD) and levels of lipid peroxidation-induced malondialdehyde in well-nourished and malnourished rats. At postnatal days 7-28, rats received no gavage treatment (naïve group), saline (vehicle group), 45 mg/kg/d of pilocarpine and/or 120 mg/kg/d of AA. CSD propagation and malondialdehyde levels were analyzed at 34-40 days. The pilocarpine group presented with lower CSD velocities, while AA groups exhibited higher CSD velocities and augmented malondialdehyde levels compared with controls. The co-administration of AA partially antagonized the pilocarpine CSD effects, but did not revert it to control levels. Malnutrition increased CSD amplitude and velocity in comparison to the well-nourished condition. The electrocorticogram (ECoG) amplitude increased after CSD (ECoG potentiation) when compared with the baseline amplitude before CSD. However, no intergroup difference was observed in this CSD-related ECoG potentiation. The results support the hypothesis of a pilocarpine/ascorbic acid interaction in the immature rat brain and might help further the understanding of this interaction on neuronal electrical activity and oxidative stress.
Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cortical Spreading Depression; Drug Interactions; Electrocorticography; Lipid Peroxidation; Male; Malnutrition; Malondialdehyde; Muscarinic Agonists; Oxidative Stress; Pilocarpine; Rats, Wistar
PubMed: 30232044
DOI: 10.1016/j.brainresbull.2018.09.008