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PubMed2000

The lesional and epileptogenic consequences of lithium-pilocarpine-induced status epilepticus are affected by previous exposure to isolated seizures: effects of amygdala kindling and maximal electroshocks.

In temporal lobe epilepsy, the occurrence of seizures seems to correlate with the presence of lesions underlying the establishment of a hyperexcitable circuit. However, in the lithium-pilocarpine model of epilepsy, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). To determine whether or not we could protect the brain from lesions and epileptogenesis induced by status epilepticus and identify cerebral structures involved in the genesis of epilepsy, we studied the effects of the chronic exposure to non-deleterious seizures, either focalized with secondary generalization (amygdala kindling, kindled-pilocarpine rats), or primary generalized (ear-clip electroshocks, electroshock-pilocarpine rats) on neuronal damage and epileptogenesis induced by lithium-pilocarpine status epilepticus. These animals were compared to rats subjected to status epilepticus but not pretreated with seizures (sham-kindled-pilocarpine or sham-electroshock-pilocarpine rats). Compared to sham-pilocarpine rats, neuronal damage was prevented in the limbic system of the kindled-pilocarpine rats, except in the hilus of the dentate gyrus and the entorhinal cortex, while it was enhanced in rats pretreated with electroshocks, mainly in the entorhinal and perirhinal cortices. Most sham-kindled- and sham-electroshock-pilocarpine rats (92-100%) developed recurrent seizures after a silent period of 40-54days. Likewise, all kindled-pilocarpine rats developed spontaneous seizures after the same latency as their sham controls, while only two of 10 electroshock-pilocarpine rats became epileptic after a delay of 106-151days. The present data show that the apparent antiepileptic properties of electroshocks correlate with extensive damage in midbrain cortical regions, which may prevent the propagation of seizures from the hippocampus and inhibit their motor expression. Conversely, the extensive neuroprotection of the limbic system but not the hilus and entorhinal cortex provided by amygdala kindling does not prevent epileptogenesis. Thus, the hilus, the entorhinal and/or perirhinal cortex may be key structure(s) for the establishment of epilepsy.

Amygdala↗

PubMed1989

Influence of ophthalmic ointments on the penetration of pilocarpine drops.

To evaluate the influence of prior administered ointments upon the intraocular penetration of drops, we applied either a combination antibiotic ointment, a combination antibiotic-steroid ointment, or a lubricant ointment at different time periods before instillation of 2% pilocarpine drops into rabbit eyes. The level of pilocarpine measured in aqueous humor at one hour was compared to the level achieved in eyes without ointment application. No change was found in pilocarpine levels following application of the lubricant ointment. Pilocarpine concentrations were significantly lower (38%-48%) in animals receiving the antibiotic ointment at 5 or 15 minutes before pilocarpine drops. Pilocarpine levels also were decreased significantly when the steroid-antibiotic ointment was applied 15, 30 or 60 minutes before the drops. To verify these effects at other time periods, ointments were applied 15 minutes before pilocarpine drops and aqueous humor samples aspirated at 30 minutes or two hours. A 22% decrease in aqueous humor pilocarpine was found at 30 minutes with both the antibiotic and steroid-antibiotic combination; no effect was observed at two hours. To determine the influence of each drug component within the ointment on the penetration of pilocarpine, solutions of dexamethasone, neomycin, bacitracin and polymyxin B were mixed individually with pilocarpine drops and applied into the animal eyes. Bacitracin and polymyxin B significantly reduced one-hour pilocarpine levels in aqueous humor; however, no significant effect was observed with either neomycin or dexamethasone.

Animals↗

PubMed1994

A comparison of the efficacy of various metipranolol-pilocarpine combinations in patients with ocular hypertension and primary open-angle glaucoma.

We compared the ocular hypotensive effects of four fixed-dose metipranolol-pilocarpine combinations in nineteen ocular hypertensive subjects and glaucoma patients. Each patient was tested with all of the study medications: vehicle alone, 0.1% metipranolol HCl + 2% pilocarpine HCl, 0.1% metipranolol HCl + 4% pilocarpine HCl, 0.3% metipranolol HCl + 2% pilocarpine HCl, and 0.3% metipranolol HCl + 4% pilocarpine HCl, in a single dose, randomized, double-masked, cross-over placebo-controlled trial. In addition, another eight age and baseline intraocular pressure (IOP)-matched subjects received 0.1% or 0.3% metipranolol HCl, while a similar group of 14 volunteers received 2% or 4% pilocarpine HCl. A two week washout period was instituted between the various groups of treatments. All four metipranolol-pilocarpine combinations were more effective than placebo or either medication alone in reducing the average IOP for up to 8 hours (p < 0.05 for each treatment group). Metipranolol HCl 0.3%, regardless of the pilocarpine concentration, demonstrated the most significant IOP lowering effect, reducing the IOP by 4.9 mm Hg or about 20% from baseline. However, 0.1% metipranolol HCl in combination with 4% pilocarpine HCl was found almost as effective with a 18.5% reduction in IOP from baseline, but a shorter duration of action. In conclusion, all metipranolol-pilocarpine combinations were more efficacious than either medication alone in a single-dose trial. Additional multiple-dose studies are needed to determine the long-term effectiveness and tolerance of combining 0.3% metipranolol HCl with either 2% or 4% pilocarpine HCl.

Adult↗

PubMed1995

Sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) in eyedrops improves the tolerability of a topically applied pilocarpine prodrug in rabbits.

The effects of a novel, modified beta-cyclodextrin (SBE4-beta-CD; a variably substituted sulfobutyl ether with an average degree of substitution of four) on eye irritation and miotic response of an ophthalmically applied pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, in albino rabbits were studied. Compared to the commercial pilocarpine eyedrop solution (163 mM, equivalent to 3.4% pilocarpine), 12-24 mM pilocarpine prodrug solutions (equivalent to 0.5-1.0% pilocarpine, respectively) decreased peak miotic intensity (Imax) and increased the time to reach peak (tmax), but did not significantly affect values for the area under the miosis versus time curves (AUC), i.e. 12-24 mM pilocarpine prodrug appeared to be equivalent to 163 mM pilocarpine. Ocularly applied 12-24 mM pilocarpine prodrug solutions, however, were more irritating than a commercial pilocarpine eyedrop solution. Coadministered SBE4-beta-CD significantly decreased the eye irritation of the pilocarpine prodrug solutions. Coadministered SBE4-beta-CD did not affect the miotic response of prodrug solution when the molar ratio of SBE4-beta-CD to prodrug was low. However, increasing the molar ratio of SBE4-beta-CD to prodrug decreased the Imax and AUC values. The results show that eye irritation of the pilocarpine prodrug is prevented by levels of SBE4-beta-CD that do not affect the apparent ocular absorption of the prodrug.

Absorption↗

PubMed1994

Pilocarpine-induced relaxation of rat tail artery by a non-cholinergic mechanism and in the absence of an intact endothelium.

1. The partial muscarinic agonist, pilocarpine, evoked concentration-dependent relaxation with an EC50 of 2.4 x 10(-3) M in isolated segments of rat tail artery that were constricted with phenylephrine (10(-8) to 2 x 10(-7) M). Acetylcholine also evoked concentration-dependent relaxation but was more potent than pilocarpine (EC50, 6.5 x 10(-7) M). 2. The concentration-relaxation curves for pilocarpine were not affected by the muscarinic antagonists, atropine (10(-9) M) or pirenzepine (5 x 10(-7) M), while the concentration-relaxation curves for acetylcholine-evoked relaxation of the same tissues were shifted some 10 fold to the right by these concentrations of atropine and pirenzepine. 3. Acetylcholine failed to evoke relaxation following removal of the endothelium. The smooth muscle of the rat tail artery was some 10 fold more sensitive to the relaxing action of pilocarpine following denudation of the endothelium. 4. The effects of pilocarpine and acetylcholine on membrane potential were studied in tissues that were depolarized to -39 +/- 1 mV with phenylephrine (5 x 10(-8) to 2 x 10(-7) M). In intact tissues, pilocarpine caused hyperpolarization, an effect that persisted in the presence of muscarinic antagonists. Acetylcholine also evoked hyperpolarization. 5. Following removal of the endothelium, pilocarpine (10(-5) to 10(-3) M) evoked hyperpolarization in 6 of 15 preparations and a decrease in the frequency of action potentials in the remainder. Both of these responses were associated with relaxation. 6. The effects of pilocarpine were compared with other agents that evoke endothelium-independent relaxation. The concentration-relaxation curves in response to pilocarpine and nitroprusside were shifted to the right by ferricyanide (10-5 M) and methylene blue (10-5 M). Glibenclamide (10-6 M) was without effect on the hyperpolarization and relaxation evoked by pilocarpine (10' to 10- M).7. Thus, pilocarpine evokes relaxation of rat tail artery independently of the cholinergic system and it is suggested that this is achieved by decreasing the frequency of action potentials in the smooth muscle.

Acetylcholine↗

PubMed1994

The effect of a modified beta-cyclodextrin, SBE4-beta-CD, on the aqueous stability and ocular absorption of pilocarpine.

In the present study, the effects of a novel, modified beta-cyclodextrin derivative (SBE4-beta-CD; a variably substituted sulfobutyl ether of beta-cyclodextrin with an average degree of substitution of four) on the aqueous stability of pilocarpine and on its ocular absorption in albino rabbits were studied. For stability reasons, commercial pilocarpine eyedrops are formulated at pH 4-5, a pH range where pilocarpine (pKa approximately 7) is almost completely ionized. As shown in the present and past studies, increasing the pH of the pilocarpine solution from 4.5 to 7.0 increases the ocular absorption of pilocarpine. SBE4-beta-CD increased the aqueous stability of pilocarpine (0.36 mM) at pH 7.0 (4 degrees C, projected values from Arrhenius data at 25 degrees C, 37 degrees C and 50 degrees C); in the absence of SBE4-beta CD, t90% was 236 days. In the presence of 1 mM and 25 mM of SBE4-beta-CD, t90% was 382 days and 2054 days, respectively suggesting that indeed, pilocarpine does interact with SBE4-beta-CD. SBE4-beta-CD did not damage the corneal epithelium in vitro and was well-tolerated by the rabbit eye in vivo. Coadministered SBE4-beta-CD did not significantly affect the miotic response of pilocarpine solutions at pH values of 4.5 or 7.0 when the molar ratio of SBE4-beta-CD to pilocarpine was between 0.2:1-7:1. The effect of the coadministered SBE4-beta-CD on the miotic response of pilocarpine solutions was also compared to that of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) which has recently been suggested to increase ocular bioavailability of pilocarpine in rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1999

Interaction of pilocarpine with latanoprost in patients with glaucoma and ocular hypertension.

PURPOSE: To study any interaction between pilocarpine and latanoprost when administered together, and to determine the optimal timing of dosage to maximize reduction of intraocular pressure (IOP). METHODS: Nineteen adult patients with either primary open-angle glaucoma or ocular hypertension participated in a single-center, prospective case study with masked observer. After a baseline measurement of IOP during treatment with latanoprost was obtained, initial treatment with pilocarpine three times daily was added without bedtime administration. This was followed by three different dose regimens in which pilocarpine was administered four times daily, altering the bedtime pilocarpine dose to precede the latanoprost dose by 1 hour, or to follow it by 10 minutes or 1 hour. Intraocular pressure was measured at 8:00 AM and 75 minutes after administration of the morning dose of pilocarpine. RESULTS: Comparison of IOP at 8:00 AM with baseline showed no significant change when pilocarpine was taken three times daily, or when pilocarpine was taken four times daily when the bedtime dose preceded administration of latanoprost by 1 hour. There were significant decreases in IOP versus baseline when the bedtime dose of pilocarpine was taken simultaneously with or 1 hour after administration of latanoprost. Application of pilocarpine immediately after the 8:00 AM IOP measurement revealed a significant additional decrease in pressure. There were no significant differences between dosage schedules in the magnitude of the additional reduction in IOP. CONCLUSION: The order and timing of administration of pilocarpine and latanoprost can significantly alter their ocular hypotensive activity. Pilocarpine is most effective when administered four times daily, and when the bedtime dose is administered 1 hour after administration of latanoprost.

Aged↗

PubMed1998

[Effect of pilocarpine in tissue structures of the anterior eye segment from the aspect of its interaction with free amino acids].

On the basis of the proofs of pilocarpine interaction with free amino acids, the mechanism of this alkaloid effect in the tissue structures of the eye anterior segment is explained. Differences of colour reactions of amino acids mixtures with pilocarpine, decrease of radioactivity of Na[I125]tyrosine mixture with pilocarpine, unsteadiness of radioactivity of Na[I125]protein A mixture with pilocarpine and rise of 16 radioactivity fractions after adding pilocarpine to Na[I125]proteins A a) show the specificity of interaction of each amino acid with pilocarpine; b) give evidence of a strong covalent bond between pilocarpine and free amino acid and give rise to new biologically active metabolite; c) show non-cholinergic pathway of pilocarpine effect; d) for ophthalmo-physiological practice it is said that with respect to the rate between pilocarpine quantity and concentration and free amino acid quantity and concentration requested therapeutical effect by lower pilocarpine dose in glaucoma disease treatment might be achieved. Thus free amino acids being reactants can be identified as mechanism by which pilocarpine becomes biologically active.

Anterior Eye Segment↗

PubMed2026

Evaluation of pilocarpine effects on sweat proteome.

BACKGROUND: Sweat is increasingly recognized as a valuable, non-invasive biofluid for biomarker discovery, yet its composition depends on the stimulation method. This study aimed to determine how pharmacological induction with pilocarpine compares to physiologically induced sweat through exercise in shaping the sweat proteome. RESULTS: We analyzed thermoregulatory sweat from exercise, pilocarpine-induced sweat, and combined pilocarpine plus exercise sweat. Total protein concentrations were similar across conditions, but pilocarpine markedly increased proteomic diversity, with combined pilocarpine plus exercise sweat showing the highest number of identifications. The core sweat proteome remained stable, while pilocarpine selectively enriched low-abundance proteins involved in vesicular trafficking, cytoskeletal remodelling, and metabolism. Proteins linked to the canonical M3-Gq-PLC-Ca2+ pathway, including AQP5, CALML5, and CLIC1, were consistently enriched, confirming cholinergic activation. Pilocarpine-induced sweat also contained plasma-derived and immune-related proteins, reflecting enhanced secretion and reduced ductal reabsorption. CONCLUSIONS: Exercise yields a physiologically relevant but less complex proteome, pilocarpine-induced sweat produces a pharmacologically enriched yet biased profile, and combined pilocarpine plus exercise sweat maximizes protein detection at the expense of interpretability. These findings highlight the critical impact of stimulation paradigm on sweat proteomics and provide a reference framework for biomarker research. SIGNIFICANCE: This study employed LC-MS/MS to systematically characterize eccrine sweat and delineate how stimulation paradigms-exercise, pilocarpine, and their combination-shape its proteomic landscape. By demonstrating that pharmacological induction profoundly alters protein diversity and composition compared to physiologically induced sweat, these findings establish a critical benchmark for sweat-based biomarker research and highlight the need for paradigm-aware sampling strategies in clinical and translational contexts. Nonetheless, several methodological constraints warrant consideration: the limited sample size (five individuals per group), the exclusive inclusion of women under combined oral contraceptive treatment (21 active pills followed by 7 pill-free days), which restricts extrapolation to naturally cycling women, and the focus on healthy young adults (18-25 years), limiting generalizability to older or clinically heterogeneous populations. Despite these limitations, this work provides a foundational framework for optimizing sweat collection protocols and advancing precision approaches in non-invasive diagnostics.

Pilocarpine↗

PubMed1993

Interaction of PhXA41, a new prostaglandin analogue, with pilocarpine. A study on patients with elevated intraocular pressure.

OBJECTIVE: To evaluate the effects of PhXA41, a new prostaglandin analogue, on the intraocular pressure (IOP) in patients receiving pilocarpine treatment and the effects of pilocarpine in patients receiving PhXA41 treatment. DESIGN: Twenty patients with ocular hypertension were randomized into two parallel groups. The treatment period was 2 weeks. Ten patients in group 1 were given PhXA41 twice daily during week 1 and, in addition, pilocarpine three times daily during week 2. Ten patients in group 2 received pilocarpine three times daily during week 1 and PhXA41 twice daily in addition during week 2. PhXA41 was used in a concentration of 0.006%, and pilocarpine was given in a concentration of 2%. MAIN OUTCOME MEASURES: In group 1, the mean IOP on day 0 was 25.1 mm Hg; on day 7, 19.1 mm Hg; and on day 14, 17.6 mm Hg. In group 2, the mean IOP on day 0 was 23.8 mm Hg; on day 7, 20.4 mm Hg; and on day 14, 17.7 mm Hg. RESULTS: PhXA41 had a clinically significant IOP-lowering effect (23.4% reduction on day 7 as compared with baseline day (P < .001). The corresponding value with pilocarpine was 14.3% (P < .001). When pilocarpine was added to PhXA41, the additional IOP reduction was 7.4% (P < .01) compared with 14.2% (P < .01) when PhXA41 was added to pilocarpine. The two groups were found to have an almost equal reduction in IOP on day 14 (group 1, 29.4%; group 2, 26.6%). No serious adverse reactions were seen. Some conjunctival hyperemia in the PhXA41-treated eyes was noted on day 7, as compared with the pilocarpine-treated eyes, but there were few complaints of discomfort. CONCLUSIONS: This study indicated that PhXA41 could be useful in the treatment of glaucoma, as monotherapy, or in certain cases in combination with pilocarpine.

Aged↗

PubMed1989

Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats.

MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality.

Animals↗

PubMed1994

Repeated scopolamine injections sensitize rats to pilocarpine-induced vacuous jaw movements and enhance striatal muscarinic receptor binding.

This experiment was conducted to determine if repeated administration of the muscarinic antagonist scopolamine could increase pilocarpine-induced vacuous jaw movements and also enhance muscarinic receptor binding. Rats received daily injections of either scopolamine (0.5 mg/kg IP) or saline for 14 days. On day 15 rats received no injections of scopolamine, but did receive injections of pilocarpine (1.0, 2.0 or 4.0 mg/kg IP) or saline. After administration of pilocarpine or saline, all rats were observed for vacuous jaw movements and rearing behavior. The day after pilocarpine injections, rats were sacrificed and samples of tissue from the lateral neostriatum were removed to assess muscarinic receptor binding using 3H-QNB as the ligand. Analyses of the vacuous jaw movement data indicated that there was a significant dose-related increase in vacuous jaw movements induced by pilocarpine, and also that there was a significant enhancement of pilocarpine-induced vacuous jaw movements in rats pretreated with repeated scopolamine injections. There was not a significant scopolamine x pilocarpine interaction, suggesting that pretreatment with scopolamine produced an apparent parallel shift in the pilocarpine dose-response curve. Pilocarpine significantly suppressed rearing behavior, and scopolamine pretreatment significantly enhanced the suppression of rearing produced by pilocarpine. Analysis of the receptor binding data indicated that there was a significant increase in the number of muscarinic receptor sites (Bmax) in rats that received repeated scopolamine injections as compared to saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

The susceptibility of rats to pilocarpine-induced seizures is age-dependent.

Behavioral, electroencephalographic and morphological changes induced by systemic administration of pilocarpine hydrochloride were studied in 3-90-day-old rats. Pilocarpine, 100, 200 and 380 mg/kg, presented a characteristic array of behavioral patterns in developing rats. Hyper- or hypoactivity, tremor, loss of postural control, scratching, head bobbing and myoclonic movements of the limbs dominated the behavior in 3-9-day-old rats. No overt motor seizures were observed in this age group. More intense behavioral signs evolving in some animals to limbic seizures and status epilepticus occurred when pilocarpine was administered in 12-day-old-rats. The electrographic activity in these animals progressed from low voltage spiking registered concurrently in the hippocampus and cortex during the first week of life into localized epileptic activity in the hippocampus, which spread to cortical recordings during the second week of life. No morphological alterations were detected in the brains of 3-12-day-old rats subjected to the action of pilocarpine, 100-380 mg/kg. The adult pattern of behavioral and electroencephalographic sequelae after pilocarpine was encountered in 15-21-day-old rats. Akinesia, tremor and head bobbing progressed in 15-21-day-old rats given pilocarpine, 100-380 mg/kg, to motor limbic seizures and status epilepticus. The lethal toxicity of pilocarpine reached 50% during the third week of life. This increased susceptibility to the convulsant action of pilocarpine was characterized by a shortened latency for behavioral and electrographic signs, and an increased severity of seizures relative to older and younger rats. In 15-21-day-old rats subjected to pilocarpine-induced convulsions high voltage fast activity superposed over hippocampal theta-rhythm, progressed into high voltage spiking and spread to cortical records. The electrographic activity became well synchronized and then developed into seizures and status epilepticus. Morphological analysis of frontal forebrain sections in 15-21-day-old rats which underwent status epilepticus after pilocarpine revealed no damage or an attenuated pattern of damage. In 15-21-day-old rats which presented epilepsy-related brain damage, morphological breakdown was seen in the hippocampus, amygdala, olfactory cortex, neocortex and certain thalamic nuclei. No damage was detected in the substantia nigra and lateral thalamic nucleus. An adult pattern of the damage to the brain, in terms of extent and topography, was present in 4-5-week-old rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1986

Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: effects of intranigral 2-amino-7-phosphonoheptanoate and N-methyl-D-aspartate.

Seizures produced by pilocarpine given i.p. to rats provide an animal model for studying the initiation, spread and generalisation of convulsive activity within the forebrain. Pilocarpine, 380 mg/kg, produces a sequence of behavioural and electroencephalographic alterations indicative of motor limbic seizures and status epilepticus, which is followed by widespread damage to the limbic forebrain resembling that occurring subsequent to prolonged intractable seizures. Microinjections of a selective antagonist at the N-methyl-D-aspartate receptor, (+/-)-2-amino-7-phosphonoheptanoate, into the substantia nigra pars reticulata, bilaterally, protects against the behavioural, electrographic and morphological features of seizures produced by pilocarpine, 380 mg/kg, with an ED50 of 0.0007 mumol (0.0004-0.0011). Microinjections of (+/-)-2-amino-7-phosphonoheptanoate, 0.005 or 0.01 mumol, into the substantia nigra pars compacta or into the dorsal part of mid-anterior striatum do not modify the electrographic and morphological sequelae of pilocarpine, 380 mg/kg. In rats pretreated with microinjections of N-methyl-D-aspartate into the substantia nigra pars reticulata, a non-convulsive dose of pilocarpine, 100 mg/kg, results in recurrent motor limbic seizures and status epilepticus. The ED50 of N-methyl-D-aspartate for the generation of seizures after pilocarpine, 100 mg/kg, is 0.0014 mumol (0.001-0.0019). Electrographic monitoring shows a pattern and sequence of evolution of convulsant activity within the hippocampus and cortex similar to that produced with pilocarpine, 380 mg/kg, alone. Morphological examination of brains from rats treated with N-methyl-D-aspartate in the substantia nigra pars reticulata and subsequently given pilocarpine, 100 mg/kg, which underwent status epilepticus, reveals widespread damage to the amygdala, thalamus, olfactory cortex, substantia nigra, neocortex, and hippocampus. Microinjections of N-methyl-D-aspartate, 0.002 mumol, into either the substantia nigra pars compacta or dorsal striatum, bilaterally, do not augment seizures produced by pilocarpine, 100 mg/kg. The results indicate that the threshold for pilocarpine-induced seizures in rats is modulated by excitatory amino acid neurotransmission within the substantia nigra pars reticulata.

2-Amino-5-phosphonovalerate↗

PubMed2005

Effects of AV3V lesion on pilocarpine-induced pressor response and salivary gland vasodilation.

The cholinergic agonist pilocarpine injected intraperitoneally (ip) increases mean arterial pressure (MAP) and superior mesenteric (SM) vascular resistance and reduces submandibular/sublingual gland (SSG) vascular resistance. In the present study, we investigated the effects of electrolytic lesions of the anteroventral third ventricle (AV3V) region on the changes in MAP, SM, and SSG vascular resistances induced by ip pilocarpine. Male Holtzman rats anesthetized with urethane (1.0 g/kg) and chloralose (60 mg/kg) were submitted to sham or electrolytic AV3V lesions and had pulsed Doppler flow probes implanted around the arteries. Contrary to sham rats, in 1-h and 2-day AV3V-lesioned rats, pilocarpine (4 micromol/kg) ip decreased MAP (-41 +/- 4 and -26 +/- 4 mm Hg, respectively, vs. sham: 19 +/- 4 mm Hg) and SM (-48 +/- 11 and -45 +/- 10%, respectively, vs. sham: 41 +/- 10%) and hindlimb vascular resistances (-65 +/- 32 and -113 +/- 29%, respectively, vs. sham: 19 +/- 29%). In 7-day AV3V-lesioned rats, pilocarpine produced no changes on MAP and SM and hindlimb vascular resistances. Similar to sham rats, pilocarpine reduced SSG vascular resistance 1 h after AV3V lesions (-46 +/- 6%, vs. sham: -40 +/- 6%), but it produced no effect 2 days after AV3V lesions and increased SSG vascular resistance (37 +/- 6%) in 7-day AV3V-lesioned rats. The responses to ip pilocarpine were similar in 15-day sham and AV3V-lesioned rats. The cholinergic antagonist atropine methyl bromide (10 nmol) iv slightly increased the pressor response to ip pilocarpine in sham rats and abolished for 40 min the fall in MAP induced by ip pilocarpine in 1-h AV3V-lesioned rats. The results suggest that central mechanisms dependent on the AV3V region are involved in the pressor responses to ip pilocarpine. Although it was impaired 2 and 7 days after AV3V lesions, pilocarpine-induced salivary gland vasodilation was not altered 1 h after AV3V lesions which suggests that this vasodilation is not directly dependent on the AV3V region.

Analysis of Variance↗

PubMed2005

Sprouting of mossy fibers and presynaptic inhibition by group II metabotropic glutamate receptors in pilocarpine-treated rat hippocampal slice cultures.

Mossy fibre sprouting (MFS) is a phenomenon observed in the epileptic hippocampus. We have studied MFS, in 7, 14 and 21 day in vitro (DIV) organotypic slice cultures, or in slice cultures treated with pilocarpine (0.5 mM) or pilocarpine and atropine (0.1 mM or 0.5 mM) for 48-72 h at 5 DIV and tested at 21 DIV. Acute application of pilocarpine directly activated hilar neurons and elicited epileptic-like discharges in CA3 pyramids and mossy cells of 5-8 DIV cultures, without causing substantial cell death, as assessed by lactate dehydrogenase measurements. Timm staining revealed increases in MFS in chronic pilocarpine-treated cultures, which was prevented by prior application of atropine. Extracellular synaptic responses were recorded in the granule cell layer and elicited by antidromic mossy fibre stimulation. The GABA(A) antagonist 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid (1 microM) induced a greater increase in the coastline bursting index in pilocarpine-treated cultures than in 21 DIV controls. However, there was no significant increase in the frequency of spontaneous or miniature synaptic events recorded in granule cells from pilocarpine-treated cultures. Granule cells were filled with biocytin and morphometric analysis revealed that the length of axon collaterals in the granule and molecular layer was longer in pilocarpine-treated cultures than in 21 DIV controls. Dual recordings between granule cells and between granule and hilar neurons showed that pilocarpine-treated cultures had a larger proportion of monosynaptic and polysynaptic connections. The group II metabotropic glutamate receptor (mGluR) agonist LY354740 (0.5 microM) suppressed excitatory but not inhibitory monosynaptic currents. LY354740 also inhibited antidromically evoked action currents in granule cells from pilocarpine- and to a lesser extent in pilocarpine and atropine-treated cultures, suggesting that group II mGluRs can reside along the axon and suppress action potential invasion. We provide direct evidence for the development of functional MFS and suggest a novel, axonal mechanism by which presynaptic group II mGluRs can inhibit selected synapses.

Animals↗

PubMed2005

Arginine vasopressin does not contribute to seizures induced by intracerebroventricularly-injected pilocarpine.

Arginine vasopressin (AVP) has been shown to contribute to the production of seizures. Here, we aimed to investigate the effects of AVP on seizures induced by intracerebroventricular (i.c.v.) injection of pilocarpine. Rats were treated with 0.2-2.4 mg/5 microl pilocarpine intracerebroventricularly, to obtain the dose-response relationship for behavioural seizures. 2.4 mg/5 microl pilocarpine induced status epilepticus in all rats and 0. 2 mg/5 microl pilocarpine did not produce any sign of seizure in any of the rats. In the second step, AVP (0.01-1000 ng/2 microl; i.c.v.) was injected 5 min before i.c.v. injection of a low dose pilocarpine (0.4 mg/5 microl) and rats were observed for percentage of status epilepticus, status epilepticus latency and behavioural seizure scores. None of the applied doses of AVP had any significant effect on seizures induced by 0.4 mg/5 microl i.c.v. pilocarpine. Subcutaneous injection of 1000 ng AVP 1h before 0.4 mg i.c.v. pilocarpine also did not produce significant difference with respect to the 0.4 mg pilocarpine group. Finally, pretreatment with neither an AVP V(1) receptor antagonist (25, 125, 250 ng/5 microl; i.c.v.) nor an AVP V(2) receptor antagonist (25, 125, 250 ng/5 microl; i.c.v.) prevented status epilepticus, induced by 2.4 mg/5 microl i.c.v. pilocarpine. We conclude that AVP does not act as a convulsant agent in centrally-induced pilocarpine seizures.

Animals↗

PubMed2005

Stimulus-driven versus pilocarpine-induced biometric changes in pseudophakic eyes.

PURPOSE: Most trials that study the lens movement of accommodative intraocular lens (IOLs) use pilocarpine to stimulate ciliary muscle contraction. The aim of this study is to assess in vivo whether a more physiologic, stimulus-driven accommodation is comparable to pilocarpine-induced IOL movement. DESIGN: Controlled patient- and examiner-masked clinical trial. PARTICIPANTS: The study population included 38 eyes with accommodative IOL implants (1CU) and a control group of 28 eyes with conventional open-loop IOLs. METHODS: A high-precision biometry technique, partial coherence interferometry, was used to measure IOL position. Anterior chamber depth was measured during physiologic (near point) and pharmacological (pilocarpine 2%) stimulation. In a subgroup of 14 1CU eyes, IOL position was determined repeatedly within 90 minutes after pilocarpine administration. A different subgroup was investigated as to the effect of cyclopentolate on IOL position. Best-corrected distance visual acuity (VA), best-corrected near VA, and distance-corrected near VA (DCNVA) were assessed using logarithm of the minimum angle of resolution charts. MAIN OUTCOME MEASURES: Anterior chamber depth change under pilocarpine and near-point-driven accommodation. RESULTS: Near-point accommodation did not induce movement of either the accommodating 1CU or the control IOLs. Pilocarpine induced a 201+/-0.137-mm anterior movement of the 1CU IOL (P<0.001), compared with no movement within the control IOL groups (P>0.05). There was no significant (P>0.05) difference in DCNVA between the accommodative and open-loop IOLs. No correlation between near point- or pilocarpine-stimulated IOL movement and DCNVA was found. Concerning the time course of movement after pilocarpine administration, most of the 1CU IOLs showed some movement 30 minutes after application. Cyclopentolate-induced ciliary muscle relaxation caused a posterior IOL movement, as compared with the relaxed state, when focusing on a distant target. CONCLUSION: Pilocarpine-induced ciliary muscle contraction seems to overestimate IOL movement relative to a monocular near-driven stimulus. Therefore, concerning IOL movement, pilocarpine may act as a superstimulus and may not adequately simulate daily life performance of accommodative IOLs. However, it may be helpful to evaluate the maximum potential of an accommodating IOL.

Accommodation, Ocular↗