l-pGlu-(2-propyl)-l-His-l-ProNH2 attenuates 4-aminopyridine-induced epileptiform activity and sodium current: a possible action of new thyrotropin-releasing hormone analog for its anticonvulsant potential

Sah, Nirnath; Rajput, Satyendra K.; Singh, Jai Vir; Meena, Chhuttan Lal; Jain, Rahul; Sikdar, Sujit Kumar; Sharma, Shyam Sundar

doi:10.1016/j.neuroscience.2011.10.008

Cited by 25 publications

(23 citation statements)

References 65 publications

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“…35–38 Vehicle (5 mL/kg), TRH or TRH like-peptides (10 μmol/kg equivalent to 3.6 mg/kg of TRH) were injected into mice (n = 8–10/group) via the tail vein. Ten minutes after injection, each mouse received PB (50 mg/kg, i.p.).…”

Section: Experimental Sectionsmentioning

confidence: 99%

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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TRH-like peptides were synthesized in which the critical N-terminus residue L-pGlu was replaced with various heteroaromatic rings, and the central residue histidine with 1-alkyl-L-histidines. All synthesized TRH-like peptides were evaluated in vitro as agonists in HEK mTRH-R1 and HEK mTRH-R2 cell lines, an expressing receptor binding assay (IC50), and cell signaling assay (EC50). The analeptic potential of the synthesized peptides was evaluated in vivo by using the antagonism of a pentobarbital-induced sleeping time. The peptides 6a, 6c and 6e were found to activate TRH-R2 with potencies (EC50) of 0.002 μM, 0.28 μM and 0.049 μM, respectively. In contrast, for signaling activation of TRH-R1, the same peptides required higher concentration of 0.414 μM, 50 μM and 19.1 μM, respectively in the FLIPR assay. The results showed that these peptides were 207, 178 and 389-fold selective towards TRH-R2 receptor subtype. In the antagonism of a pentobarbital-induced sleeping time assay, peptide 6c showed a 58.5% reduction in sleeping time. The peptide 6c exhibited high stability in rat blood plasma, a superior effect on the scopolamine-induced cognition impairment mice model, safe effects on the cardiovascular system, and general behavior using a functional observation battery (FOB).

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Section: Experimental Sectionsmentioning

confidence: 99%

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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“…NP-355 (L-pGlu-(1-benzyl)-L-His-L-ProNH(2); Fig. 7) and NP-647 (L-pGlu-(2-propyl)-L-His-L-ProNH2) were effective anti-convulsants in a number of different models of epilepsy [318][319][320]. Clearly, selective non-peptide molecules acting on TRH-R2 would have great anti-epileptic potential and their development is awaited.…”

Section: Thyrotropin-releasing Hormonementioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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“…Under stimulation with the epileptogenic factor 4AP (20 μM), the activation of cGKII by 8-Br-cGMP (500 μM) triggered paroxysmal depolarization shifts (PDSs) in pyramidal neurons in the hippocampal CA1 region. PDSs are typical of epileptiform activity, which is displayed primarily as a burst of high-frequency action potential (at least four action potentials occur in a PDS) [31]. To verify that these epileptiform discharges were truly caused by 8-Br-cGMP, we washed the brain slices with ACSF containing 4AP (20 μM) at the end of the experiment and found that the epileptiform discharges nearly disappeared (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3e). Due to the hyperexcitability of neurons under stimulation with epileptogenic agents, the burst frequency of action potentials, the frequency of PDSs, and the burst frequency of action potentials in PDSs could be measured to assess seizure severity [31]. Therefore, we calculated the following three parameters: the mean firing frequency [0.67 ± 0.14 Hz in the 4AP (20 μM) group, 1.27 ± 0.18 Hz in the 4AP (20 μM) + 8-Br-cGMP group, and 0.78 ± 0.09 Hz in the washout group, **p < 0.01, Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1

Tian

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The imbalance between excitation and inhibition is a defining feature of epilepsy. GluA1 is an AMPA receptor subunit that can strengthen excitatory synaptic transmission when upregulated in the postsynaptic membrane, which has been implicated in the pathogenesis of epilepsy. cGKII, a cGMP-dependent protein kinase, regulates the GluA1 levels at the plasma membrane. Methods: To explore the role of cGKII in epilepsy, we investigated the expression of cGKII in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model and then performed behavioral, histological, and electrophysiological analyses by applying either a cGKII agonist or inhibitor in the hippocampus of the animal model. Results: cGKII expression was upregulated in the epileptogenic brain tissues of both humans and rats. Pharmacological activation or inhibition of cGKII induced changes in epileptic behaviors in vivo and epileptic discharges in vitro. Further studies indicated that cGKII activation disrupted the balance of excitation and inhibition due to strengthened AMPAR-mediated excitatory synaptic transmission. Moreover, cGKII regulated epileptic seizures by phosphorylating GluA1 at Ser845 to modulate the expression and function of GluA1 in the postsynaptic membrane. Conclusion: These results suggest that cGKII plays a key role in seizure activity and could be a potential therapeutic target for epilepsy.

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l-pGlu-(2-propyl)-l-His-l-ProNH2 attenuates 4-aminopyridine-induced epileptiform activity and sodium current: a possible action of new thyrotropin-releasing hormone analog for its anticonvulsant potential

Cited by 25 publications

References 65 publications

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Inhibition of Cgkii Suppresses Seizure Activity and Hippocampal Excitation by Regulating the Postsynaptic Delivery of Glua1

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