- Neonatal pyridoxine administration long lastingly accelerates cortical spreading depression in male rats, without affecting anxiety-like behavior. [Journal Article]
- NNNutr Neurosci 2019 Jun 21; :1-8
- Objectives: Pyridoxine plays a key role in the development of the human nervous system. Several reports suggest that administration of high doses of pyridoxine can be helpful in improving disturbanc…
Objectives: Pyridoxine plays a key role in the development of the human nervous system. Several reports suggest that administration of high doses of pyridoxine can be helpful in improving disturbances such as anxiety and pyridoxine-dependent epilepsy, although it has also been associated with a proconvulsive action. In this study, we investigated in developing rats the effects of repeated administration of various doses of pyridoxine on anxiety-like behavior and the brain excitability-related phenomenon known as cortical spreading depression (CSD). Methods: From postnatal day (P) 7 to P27, Wistar rat pups received per gavage pyridoxine hydrochloride (1 mg/kg/day, or 5 mg/kg/day, or 10 mg/kg/day). On P60-70, the animals were tested in the elevated plus maze (EPM) to evaluate anxiety-like behavior. On P71-80, we recorded the CSD (4-hour recording session). Results: Compared with naïve (gavage-free) and saline-treated controls, pyridoxine-treated groups displayed a significant (p < 0.001) increase in CSD propagation velocity and amplitude of the CSD negative direct-current (DC)-shift, and a decrease in the CSD DC-shift duration. These effects were long-lasting and dose-dependent. In the EPM, no significant pyridoxine-associated effect was observed. Discussion: Our data demonstrate a novel action of pyridoxine on an electrical activity-related phenomenon (CSD) in the developing brain, confirming the hypothesis that the chronic treatment with pyridoxine early in life modulates CSD. Data on CSD propagation suggest that pyridoxine at a high dose might act as a prooxidant agent in the developing brain, a hypothesis that deserves further testing.
- Neuroservice proconvulsive (NS-PC) set: A new platform of electrophysiology-based assays to determine the proconvulsive potential of lead compounds. [Journal Article]
- JPJ Pharmacol Toxicol Methods 2019 Jun 14; :106587
- CONCLUSIONS: The use of reference proconvulsive compounds and AEDs validated the electrophysiological parameters to detect proconvulsive risk. Systematic evaluation of compounds with the 3 complementary endpoints increase the probability to detect seizure liability in vitro. Depending on the compound mechanism of action, only one or two of the identified parameters might be modified.
- Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model. [Journal Article]
- IJInt J Mol Sci 2019 May 20; 20(10)
- The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-…
The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit β-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843's anticonvulsive effects and suggest a possible involvement of β-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.
- Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy. [Journal Article]
- JNJ Neurosci 2019 Jul 03; 39(27):5377-5392
- Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. …
Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Whereas the fast-acting P2X channels have well-established roles driving neuroinflammation and increasing hyperexcitability, the slower-acting metabotropic P2Y receptors have received much less attention. Recent studies of P2Y1 receptor function in seizures and epilepsy have produced contradictory results, suggesting that the role of this receptor during seizure pathology may be highly sensitive to context. Here, by using male mice, we demonstrate that the metabotropic P2Y1 receptor mediates either proconvulsive or anticonvulsive responses, dependent on the time point of activation in relation to the induction of status epilepticus. P2Y1 deficiency or a P2Y1 antagonist (MRS2500) administered before a chemoconvulsant, exacerbates epileptiform activity, whereas a P2Y1 agonist (MRS2365) administered at this time point is anticonvulsant. When these drugs are administered after the onset of status epilepticus, however, their effect on seizure severity is reversed, with the antagonist now anticonvulsant and the agonist proconvulsant. This result was consistent across two different mouse models of status epilepticus (intra-amygdala kainic acid and intraperitoneal pilocarpine). Pharmacologic P2Y1 blockade during status epilepticus reduces also associated brain damage, delays the development of epilepsy and, when applied during epilepsy, suppresses spontaneous seizures, in mice. Our data show a context-specific role for P2Y1 during seizure pathology and demonstrate that blocking P2Y1 after status epilepticus and during epilepsy has potent anticonvulsive effects, suggesting that P2Y1 may be a novel candidate for the treatment of drug-refractory status epilepticus and epilepsy.SIGNIFICANCE STATEMENT This is the first study to fully characterize the contribution of a metabotropic purinergic P2Y receptor during acute seizures and epilepsy. The findings suggest that targeting P2Y1 may offer a potential novel treatment strategy for drug-refractory status epilepticus and epilepsy. Our data demonstrate a context-specific role of P2Y1 activation during seizures, switching from a proconvulsive to an anticonvulsive role depending on physiopathological context. Thus, our study provides a possible explanation for seemingly conflicting results obtained between studies of different brain diseases where P2Y1 targeting has been proposed as a potential treatment strategy and highlights that the timing of pharmacological interventions is of critical importance to the understanding of how receptors contribute to the generation of seizures and the development of epilepsy.
- A Framework Proposal to Follow-Up on Preclinical Convulsive Signals of a New Molecular Entity in First-in-Human Studies Using Electroencephalographic Monitoring. [Review]
- CPClin Pharmacol Ther 2019 Apr 16
- Traditionally, in dose-escalating first-in-human (FiH) studies, a dose cap with a 10-fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in …
Traditionally, in dose-escalating first-in-human (FiH) studies, a dose cap with a 10-fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in animals. However, the convulsive risk seen in animals does not generally translate to humans. Several lines of evidence are summarized indicating that in a dose-escalating setting, electroencephalographic epileptiform abnormalities occur at lower doses than clinical convulsive events. Therefore, we propose to consider the occurrence of epileptiform abnormalities in toxicology studies as premonitory signals for convulsions in dose-escalating FiH studies. Compared with the traditional dose-cap approach, this may allow the exploration of higher doses in FiH and, subsequently, phase II studies without compromising human safety. Similarly, the presence or absence of electroencephalographic epileptiform abnormalities may also aid the assessment of proconvulsive risk in situations of increased perpetrator burden as potentially present in pharmacokinetic and/or pharmacodynamic drug-drug interactions.
- Methadone's effects on pentylenetetrazole-induced seizure threshold in mice: NMDA/opioid receptors and nitric oxide signaling. [Journal Article]
- ANAnn N Y Acad Sci 2019 Apr 07
- Methadone is a synthetic opioid used to treat opiate withdrawal and addiction. Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impa…
Methadone is a synthetic opioid used to treat opiate withdrawal and addiction. Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impacts of acute and subchronic (three times daily for 5 days) intraperitoneal methadone treatment on pentylenetetrazole-induced clonic seizure threshold (CST) in mice, as well as the involvement of the nitric oxide, N-methyl-d-aspartate (NMDA), and μ-opioid pathways. Acute administration of different doses of methadone (0.1, 0.3, 1, and 3 mg/kg) 45 min before CST significantly decreased the seizure threshold. Additionally, pretreatment with noneffective doses of an opioid receptor antagonist (naltrexone) and NMDA receptor antagonists (ketamine and MK-801) inhibited methadone's proconvulsive activity in the acute phase, while l-NAME (a nonspecific nitric oxide synthase (NOS) inhibitor) did not affect that activity. In the subchronic phase, methadone (3 mg/kg) demonstrated an anticonvulsive effect. Although subchronic pretreatment with noneffective doses of l-NAME and 7-nitroindazole (a specific neuronal NOS inhibitor) reversed methadone's anticonvulsive activity, aminoguanidine (a specific inducible NOS inhibitor), naltrexone, MK-801, and ketamine did not change methadone's anticonvulsive characteristic. Our results suggest that NMDA and μ-opioid receptors may be involved in methadone's proconvulsive activity in the acute phase, while methadone's anticonvulsive activity may be modulated by neuronal NOS in the subchronic phase.
- Taurine potentiates the anticonvulsive effect of the GABAA agonist muscimol and pentobarbital in the immature mouse hippocampus. [Journal Article]
- EEpilepsia 2019; 60(3):464-474
- CONCLUSIONS: These observations demonstrate that taurine can indeed enhance the anticonvulsive effects of muscimol and pentobarbital, suggesting that taurine may act as a positive modulator on GABAA receptors. Thus, interfering with the modulatory taurine binding site of GABAA receptors or the interstitial taurine concentration may provide new therapeutical options for anticonvulsive therapies in neonates.
- Levetiracetam mediates subtle pH-shifts in adult human neocortical pyramidal cells via an inhibition of the bicarbonate-driven neuronal pH-regulation - Implications for excitability and plasticity modulation. [Journal Article]
- BRBrain Res 2019 May 01; 1710:146-156
- The intracellular pH (pHi) of mammalian central neurons is tightly regulated and small pHi-fluctuations can fine-tune inter-/intracellular signaling, excitability, and synaptic plasticity. The resear…
The intracellular pH (pHi) of mammalian central neurons is tightly regulated and small pHi-fluctuations can fine-tune inter-/intracellular signaling, excitability, and synaptic plasticity. The research-gap about the pHi-regulation of human brain neurons is addressed here by testing possible influences of the anticonvulsant levetiracetam (LEV). BCECF-AM-loaded neocortical pyramidal cells were fluorometrically investigated in slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal-lobe epilepsy. Recovery-slope from intracellular acidification following an ammonium prepulse (APP) was used to measure the pHi-regulation. Among twenty pyramidal cells exposed to 50 μM LEV, the resting pHi (7.09 ± 0.14) was lowered in eight (40%) neurons, on average by 0.02 ± 0.011 pH-units. In three (15%) and nine (45%) neurons, a minimal alkaline shift (0.017 ± 0.004 pH-units) and no pHi-shift occurred, respectively. The LEV-induced pHi-shifts were positively correlated with the resting pHi (r = 0.6, p = 0.006, n = 20). In five neurons, which all had responded on LEV with an acidification before, the recovery from APP-acidification was significantly delayed during LEV (p < 0.001). This inhibitory LEV-effect on pHi-regulation i) was similar to that of 200 μM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (n = 2) and ii) did not occur under nominal bicarbonate-free conditions (n = 2). Thus, LEV lowered the pHi of human neocortical pyramidal cells most likely by a weakening of the transmembrane HCO3(-)-mediated acid-extrusion. This might contribute to LEV's anticonvulsive potency. Neurons with more acidic resting pHi-values showed a minimal alkalization upon LEV providing a mechanism for paradoxical proconvulsive LEV-effects rarely observed in epilepsy patients. The significance of these subtle pHi-shifts for cortical excitability and plasticity is discussed.
- Proenkephalin Derived Peptides Are Involved in the Modulation of Mitochondrial Respiratory Control During Epileptogenesis. [Journal Article]
- FMFront Mol Neurosci 2018; 11:351
- Epilepsies are a group of common neurological diseases exerting a strong burden on patients and society, often lacking clear etiology and effective therapeutical strategies. Early intervention during…
Epilepsies are a group of common neurological diseases exerting a strong burden on patients and society, often lacking clear etiology and effective therapeutical strategies. Early intervention during the development of epilepsy (epileptogenesis) is of great medical interest, though hampered by poorly characterized epileptogenetic processes. Using the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, we investigated the functional role of the endogenous opioid enkephalin during epileptogenesis. We addressed three sequential questions: (1) How does enkephalin affect seizure threshold and how is it regulated during epileptogenesis? (2) Does enkephalin influence detrimental effects during epileptogenesis? (3) How is enkephalin linked to mitochondrial function during epileptogenesis?. In contrast to other neuropeptides, the expression of enkephalin is not regulated in a seizure dependent manner. The pattern of regulation, and enkephalin's proconvulsive effects suggested it as a potential driving force in epileptogenesis. Surprisingly, enkephalin deficiency aggravated progressive granule cell dispersion in kainic acid induced epileptogenesis. Based on reported beneficial effects of enkephalin on mitochondrial function in hypoxic/ischemic states, we hypothesized that enkephalin may be involved in the adaptation of mitochondrial respiration during epileptogenesis. Using high-resolution respirometry, we observed dynamic improvement of hippocampal mitochondrial respiration after kainic acid-injections in wild-type, but not in enkephalin-deficient mice. Thus, wild-type mice displayed higher efficiency in the use of mitochondrial capacity as compared to enkephalin-deficient mice. Our data demonstrate a Janus-headed role of enkephalin in epileptogenesis. In naive mice, enkephalin facilitates seizures, but in subsequent stages it contributes to neuronal survival through improved mitochondrial respiration.
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- Carvacrol mitigates proconvulsive effects of lipopolysaccharide, possibly through the hippocampal cyclooxygenase-2 inhibition. [Journal Article]
- MBMetab Brain Dis 2018; 33(6):2045-2050
- Systemic injection of LPS changes neuronal excitability and increase susceptibility for convulsions. Carvacrol exerts neuroprotective and antiepileptic effects in animal models. Herein, we investigat…
Systemic injection of LPS changes neuronal excitability and increase susceptibility for convulsions. Carvacrol exerts neuroprotective and antiepileptic effects in animal models. Herein, we investigated the anticonvulsive effect of carvacrol on LPS induced seizure severity and possible involvement of the hippocampal COX-1 and -2 activities in this effect. Adult male wistar rats were used. LPS was injected (400 μg/kg; i.p.) four hours before the PTZ (80 mg/kg; i.p.) injection. Carvacrol was injected (100 mg/kg; i.p.) immediately after the LPS injection. Following the PTZ injection, behavioral seizures were observed for 30 min. Latency and duration for each stage were recorded for analysis. Rats divided into seven groups: (1) PTZ, (2) LPS + PTZ, (3) carvacrol + PTZ, (4) LPS + carvacrol + PTZ, (5) LPS, (6) carvacrol, (7) intact. At the end of the experimental procedure the hippocampus of all animals were extracted to measure COX- 1 and 2 levels using the ELISA. LPS injection four hours before the PTZ injection were significantly reduced latency to seizure stages 3-5 and increased duration of the stage 5 in compare with PTZ group (p < 0.05). Carvacrol significantly reduced these effects of LPS on seizure susceptibility (p < 0.05). However, injection of carvacrol alone before the PTZ injection did not significantly affect seizure indexes in compare with PTZ group. Additionally, LPS significantly increased hippocampal level COX-2 but not COX-1 (p < 0.01) and carvacrol significantly attenuates this effect of LPS (p < 0.001). Carvacrol prevents the proconvulsant effect of LPS possibly through the inhibition of the COX-2 increased activity.