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The Cochrane Database of Systematic... Oct 2015This is an updated version of the original Cochrane review on parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (published in... (Review)
Review
BACKGROUND
This is an updated version of the original Cochrane review on parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (published in Issue 3, 2007). Salivary gland dysfunction is a predictable side effect of radiotherapy to the head and neck region. Pilocarpine hydrochloride (a choline ester) is licensed in many countries for the treatment of radiation-induced salivary gland dysfunction. Other parasympathomimetics have also been used 'off licence' in the treatment of this condition.
OBJECTIVES
To determine the efficacy and tolerability of parasympathomimetic drugs in the treatment of radiation-induced salivary gland dysfunction (specifically radiation-induced xerostomia).
SEARCH METHODS
For this update, we ran searches of the Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 6), MEDLINE, EMBASE, and CINAHL in July 2015. We checked the reference lists of retrieved articles for additional studies, contacted experts in the field for unpublished and ongoing trials, and contacted relevant pharmaceutical companies for unpublished and ongoing trials.
SELECTION CRITERIA
The selection criteria for the review were: 1) randomised controlled trials; 2) people suffering from radiation-induced salivary gland dysfunction; 3) people treated with parasympathomimetic drugs; and 4) assessable data available on primary outcome measure.
DATA COLLECTION AND ANALYSIS
The two review authors independently collected data from the full-text version of relevant papers including: 1) citation details; 2) participants; 3) interventions; 4) assessments; 5) outcomes (that is efficacy, tolerability); and 6) quality issues.Due to a lack of appropriate data, we were unable to perform a meta-analysis.
MAIN RESULTS
In the original review, three studies, including a total of 298 participants, fulfilled the inclusion criteria. All three studies involved the use of pilocarpine hydrochloride. We have included no additional studies in the update of the review; we have excluded eight additional studies.The data suggest that pilocarpine hydrochloride is more effective than placebo and at least as effective as artificial saliva. The response rate was 42% to 51%. The time to response was up to 12 weeks. The overall side effect rate was high, and side effects were the main reason for withdrawal (6% to 15% of participants taking 5 mg three times a day had to withdraw). The side effects were usually the result of generalised parasympathomimetic stimulation (for example sweating, headaches, urinary frequency, vasodilatation). Response rates were not dose dependent, but side effect rates were dose dependent.
AUTHORS' CONCLUSIONS
There is limited evidence to support the use of pilocarpine hydrochloride in the treatment of radiation-induced xerostomia. Currently, there is little evidence to support the use of other parasympathomimetic drugs in the treatment of radiation-induced xerostomia. Available studies suggest that approximately half of patients will respond, but side effects can be problematic. The conclusions of the update are the same as the conclusions of the original review, since no new relevant studies have been published in the interim.
Topics: Humans; Muscarinic Agonists; Parasympathomimetics; Pilocarpine; Radiation Injuries; Randomized Controlled Trials as Topic; Saliva, Artificial; Salivary Glands; Xerostomia
PubMed: 26436597
DOI: 10.1002/14651858.CD003782.pub3 -
Neurobiology of Disease May 2023Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models.... (Review)
Review
Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models. Interictal activity, which is recorded with cortical and intracerebral EEG recordings, comprises spikes, sharp waves and high-frequency oscillations, and has been used in clinical practice to identify the epileptic zone. However, its relation with seizures remains debated. Moreover, it is unclear whether specific EEG changes in interictal activity occur during the time preceding the appearance of spontaneous seizures. This period, which is termed "latent", has been studied in rodent models of MTLE in which spontaneous seizures start to occur following an initial insult (most often a status epilepticus induced by convulsive drugs such as kainic acid or pilocarpine) and may mirror epileptogenesis, i.e., the process leading the brain to develop an enduring predisposition to seizure generation. Here, we will address this topic by reviewing experimental studies performed in MTLE models. Specifically, we will review data highlighting the dynamic changes in interictal spiking activity and high-frequency oscillations occurring during the latent period, and how optogenetic stimulation of specific cell populations can modulate them in the pilocarpine model. These findings indicate that interictal activity: (i) is heterogeneous in its EEG patterns and thus, presumably, in its underlying neuronal mechanisms; and (ii) can pinpoint to the epileptogenic processes occurring in focal epileptic disorders in animal models and, perhaps, in epileptic patients.
Topics: Animals; Humans; Epilepsy, Temporal Lobe; Pilocarpine; Seizures; Epilepsies, Partial; Epilepsy; Electroencephalography
PubMed: 36907521
DOI: 10.1016/j.nbd.2023.106065 -
The Journal of Physiology Dec 2020Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca...
KEY POINTS
Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca signalling in many aspects of epilepsy but the diversity of Ca channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures.
ABSTRACT
Store-operated Orai1 channels are a major mechanism for Ca entry in many cells and mediate numerous functions including gene expression, cytokine production and gliotransmitter release. Orai1 is expressed in many regions of the mammalian brain; however, its role in regulating neuronal excitability, synaptic function and brain disorders has only now begun to be investigated. To investigate a potential role of Orai1 channels in status epilepticus induced by chemoconvulsants, we examined acute seizures evoked by intraperitoneal injections of kainic acid (KA) and pilocarpine in mice with a conditional deletion of Orai1 (or its activator STIM1) in the brain. Brain-specific Orai1 and STIM1 knockout (KO) mice exhibited significantly stronger seizures (P = 0.00003 and P < 0.00001), and higher chemoconvulsant-induced mortality (P = 0.02) compared with wildtype (WT) littermates. Electrophysiological recordings in hippocampal brain slices revealed that KA stimulated the activity of inhibitory interneurons in the CA1 hippocampus (P = 0.04) which failed to occur in Orai1 KO mice. Further, KA and pilocarpine increased the frequency of spontaneous IPSCs in CA1 pyramidal neurons >twofold (KA: P = 0.04; pilocarpine: P = 0.0002) which was abolished in Orai1 KO mice. Mice with selective deletion of Orai1 in GABAergic neurons alone also showed stronger seizures to KA (P = 0.001) and pilocarpine (P < 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.
Topics: Animals; Hippocampus; Kainic Acid; Mice; ORAI1 Protein; Pilocarpine; Pyramidal Cells; Seizures
PubMed: 32851638
DOI: 10.1113/JP280119 -
Journal of Neurophysiology May 2023Emerging evidence suggests that the medial septum can control seizures occurring in focal epileptic disorders, thus representing a therapeutic target. Therefore, we...
Emerging evidence suggests that the medial septum can control seizures occurring in focal epileptic disorders, thus representing a therapeutic target. Therefore, we investigated whether continuous optogenetic activation of inhibitory parvalbumin (PV)-positive interneurons in the medial septum can reduce the occurrence of spontaneous seizures in the pilocarpine model of mesial temporal lobe epilepsy (MTLE). Light pulses (450 nm, 25 mW, 20-ms pulse duration) were delivered at 0.5 Hz (5 min ON, 10 min OFF) with a laser diode fiber light source between and after status epilepticus (SE) in PV-ChR2 mice ( = 8). Seizure rates were significantly lower during time periods of optogenetic stimulation () compared with before implementation of optogenetics () ( < 0.05). Moreover, between and after SE seizure rates were still significantly lower compared with before optogenetic stimulation (i.e., between and ) ( < 0.05). No seizures were recorded between and in all animals, and no seizures occurred up to 3 days after the end of optogenetic stimulation (). Our findings indicate that activation of PV interneurons in the medial septum abates seizures in the pilocarpine model of MTLE. Moreover, the persisting anti-ictogenic effects suggest that stimulation of the medial septum could alter the progression of MTLE. The medial septum could represent a therapeutic target to treat patients with focal epilepsy. In this study, we show that optogenetic activation of inhibitory parvalbumin-positive interneurons in the medial septum can block spontaneous seizures and prevents their reoccurrence for ∼5 days after the end of stimulation. Our findings suggest that the anti-ictogenic effects induced by stimulation of the medial septum could also alter the progression of mesial temporal lobe epilepsy.
Topics: Mice; Animals; Epilepsy, Temporal Lobe; Optogenetics; Pilocarpine; Parvalbumins; Status Epilepticus; Hippocampus; Disease Models, Animal
PubMed: 37073973
DOI: 10.1152/jn.00111.2023 -
Epilepsy & Behavior : E&B Jan 2018Temporal lobe epilepsy (TLE) is the most frequent and medically refractory type of epilepsy in humans. In addition to seizures, patients with TLE suffer from behavioral...
Temporal lobe epilepsy (TLE) is the most frequent and medically refractory type of epilepsy in humans. In addition to seizures, patients with TLE suffer from behavioral alterations and cognitive deficits. Poststatus epilepticus model of TLE induced by pilocarpine in rodents has enhanced the understanding of the processes leading to epilepsy and thus, of potential targets for antiepileptogenic therapies. Clinical and experimental evidence suggests that inflammatory processes in the brain may critically contribute to epileptogenesis. Statins are inhibitors of cholesterol synthesis, and present pleiotropic effects that include antiinflammatory properties. We aimed the present study to test the hypothesis that atorvastatin prevents behavioral alterations and proinflammatory state in the early period after pilocarpine-induced status epilepticus. Male and female C57BL/6 mice were subjected to status epilepticus induced by pilocarpine and treated with atorvastatin (10 or 100mg/kg) for 14days. Atorvastatin slightly improved the performance of mice in the open-field and object recognition tests. In addition, atorvastatin dose-dependently decreased basal and status epilepticus-induced levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ) and increased interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex. The antiinflammatory effects of atorvastatin were qualitatively identical in both sexes. Altogether, these findings extend the range of beneficial actions of atorvastatin and indicate that its antiinflammatory effects may be useful after an epileptogenic insult.
Topics: Animals; Anti-Inflammatory Agents; Atorvastatin; Cerebral Cortex; Cognition Disorders; Convulsants; Disease Models, Animal; Epilepsy; Female; Gene Expression Regulation; Hippocampus; Humans; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Pilocarpine; Seizures; Status Epilepticus
PubMed: 29186698
DOI: 10.1016/j.yebeh.2017.10.021 -
International Journal of Molecular... Sep 2013This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a... (Review)
Review
This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions.
Topics: Animals; Convulsants; Electric Stimulation Therapy; Flurothyl; Humans; Kainic Acid; Neurodegenerative Diseases; Perforant Pathway; Pilocarpine; Status Epilepticus
PubMed: 24013377
DOI: 10.3390/ijms140918284 -
International Journal of Molecular... Apr 2020Epilepsy is a devastating neurological condition exhibited by repeated spontaneous and unpredictable seizures afflicting around 70 million people globally. The basic...
Epilepsy is a devastating neurological condition exhibited by repeated spontaneous and unpredictable seizures afflicting around 70 million people globally. The basic pathophysiology of epileptic seizures is still elusive, reflecting an extensive need for further research. Developing a novel animal model is crucial in understanding disease mechanisms as well as in assessing the therapeutic target. Most of the pre-clinical epilepsy research has been focused on rodents. Nevertheless, zebrafish disease models are relevant to human disease pathophysiology hence are gaining increased attention nowadays. The current study for the very first time developed a pilocarpine-induced chronic seizure-like condition in adult zebrafish and investigated the modulation in several neuroinflammatory genes and neurotransmitters after pilocarpine exposures. Seizure score analysis suggests that compared to a single dose, repeated dose pilocarpine produces chronic seizure-like effects maintaining an average seizure score of above 2 each day for a minimum of 10 days. Compared to the single dose pilocarpine treated group, there was increased mRNA expression of HMGB1, TLR4, TNF-α, IL-1, BDNF, CREB-1, and NPY; whereas decreased expression of NF-κB was upon the repeated dose of pilocarpine administration. In addition, the epileptic group demonstrates modulation in neurotransmitters levels such as GABA, Glutamate, and Acetylcholine. Moreover, proteomic profiling of the zebrafish brain from the normal and epileptic groups from LCMS/MS quantification detected 77 and 13 proteins in the normal and epileptic group respectively. Summing up, the current investigation depicted that chemically induced seizures in zebrafish demonstrated behavioral and molecular alterations similar to classical rodent seizure models suggesting the usability of adult zebrafish as a robust model to investigate epileptic seizures.
Topics: Animals; Chromatography, Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Gene Regulatory Networks; Male; NF-kappa B; Neurotransmitter Agents; Pilocarpine; Proteomics; Seizures; Tandem Mass Spectrometry; Zebrafish; Zebrafish Proteins
PubMed: 32260203
DOI: 10.3390/ijms21072492 -
Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy.Scientific Reports Sep 2021Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein,...
Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood-brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.
Topics: Animals; Anticonvulsants; Biomarkers; Datasets as Topic; Disease Models, Animal; Drug Discovery; Epilepsy, Temporal Lobe; Gene Expression Regulation; Hippocampus; Humans; Interneurons; Male; Mice; Pilocarpine; Pyramidal Cells; RNA-Seq; Single-Cell Analysis; Temporal Lobe
PubMed: 34580351
DOI: 10.1038/s41598-021-98534-3 -
Molecules (Basel, Switzerland) Nov 2021Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to...
Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly ( < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.
Topics: Animals; Anticonvulsants; Chondroitin Sulfates; Male; Mice; Molecular Docking Simulation; Neuroprotective Agents; Oxidative Stress; Pentylenetetrazole; Pilocarpine; Seizures; Status Epilepticus; Valproic Acid
PubMed: 34833865
DOI: 10.3390/molecules26226773 -
The British Journal of Ophthalmology Jan 1994Apraclonidine and pilocarpine have been shown to be effective in reducing the incidence of intraocular pressure (IOP) spikes following argon laser trabeculoplasty. An... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Apraclonidine and pilocarpine have been shown to be effective in reducing the incidence of intraocular pressure (IOP) spikes following argon laser trabeculoplasty. An additional reduction in the incidence of acute pressure rise might theoretically be expected by combining these two effective agents. In a prospective randomised study we compared the ability of apraclonidine and pilocarpine alone and in combination to prevent post laser pressure spikes. Patients receiving regular pilocarpine to either eye were excluded. Seventy five eyes received either apraclonidine (26 eyes), pilocarpine (23 eyes), or both drugs (26 eyes). Apraclonidine 1% was instilled 1 hour before and immediately after, and pilocarpine 4% immediately after trabeculoplasty. IOP was measured before and at 1, 2, and 3 hours following trabeculoplasty. In only two (8%) eyes receiving combined treatment was a pressure rise observed. This frequency was significantly lower than that seen in eyes treated with apraclonidine alone (38%), or pilocarpine alone (39%). The mean fall in IOP at 1, 2, and 3 hours was significantly greater in those eyes receiving combined treatment than in the other two groups.
Topics: Adrenergic beta-Agonists; Aged; Aged, 80 and over; Blood Pressure; Clonidine; Glaucoma, Open-Angle; Heart Rate; Humans; Intraocular Pressure; Laser Therapy; Middle Aged; Pilocarpine; Prospective Studies; Trabeculectomy
PubMed: 7906539
DOI: 10.1136/bjo.78.1.30