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The state in Islam is founded on certain principles which, according to the faith of a Muslim, are laid down in the Qur’an and Sunnah of the Holy Prophet. The first principle is that all authority in the universe vests in Allah, Who is the Omnipotent and Omnipresent Creater of the universe. Thus, according to a Muslim’s faith Allah alone must be obeyed to the exclusion of all others, and obedience may be rendered to man only under Allah’s command in the case of the Prophets whereunder rendering obedience is in fact to Allah and not to human beings. The second principle is that the law has already been laid down by Allah in the form of commands of what is good and what is evil, in the Qur’an, which is the pure word of Allah whereas Sunnah of the Holy Prophet is the authoritative exposition of the Qur’an. These commands have been sent in the form of revelation from time to time to the Prophets for the guidance of mankind, the last being the Holy Prophet Muhammad (Peace be upon him) through whom the faith had been completed and perfkcted in the Qur’an. Allah has already placed in the nature of man the knowledge of good and evil and has furhter clarified the distinction between good and evil in the Qur’an. Thus, the law of Allah, properly called, consists of Awumar and Nawuhi (the positive and negative injunctions of the Qur’an) and it is on this basis that according to a Muslim’s faith all legislation has already been made by Allah and every Muslim is enjoined to promote good and to suppress evil. In the Qur’an no mode of lite is prescribed for a politically and economically subjugated Muslim community. In Sura 4: Verse 59 the Muslims are commanded to obey Allah, to obey the Holy Prophet and those having authority over them, who are from amongst them. Consequently, a Muslim is to render obedience firstly to Allah, then to the Holy Prophet, lastly to those members of the Muslim comminity who command authority over him provided that they are acting only in execution of the commands of Allah and the Holy Prophet. So, it is evident that rendering obedience to those who command authority over ...

Kv2.1 channels mediate cell death-enabling loss of cytosolic potassium in neurons following plasma membrane insertion at somatodendritic clusters. Overexpression of the carboxyl terminus (CT) of the cognate channel Kv2.2 is neuroprotective by disrupting Kv2.1 surface clusters. Here, we define a seven-amino acid declustering domain within Kv2.2 CT (DP-2) and demonstrate its neuroprotective efficacy in a murine ischemia-reperfusion model. TAT-DP-2, a membrane-permeable derivative, induces Kv2.1 surface cluster dispersal, prevents post-injurious pro-apoptotic potassium current enhancement, and is neuroprotective in vitro by disrupting the association of Kv2.1 with VAPA. TAT-DP-2 also induces Kv2.1 cluster dispersal in vivo in mice, reducing infarct size and improving long-term neurological function following stroke. We suggest that TAT-DP-2 induces Kv2.1 declustering by disrupting Kv2.1-VAPA association and scaffolding sites required for the membrane insertion of Kv2.1 channels following injury. We present the first evidence of targeted disruption of Kv2.1-VAPA association as a neuroprotective strategy following brain ischemia., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

We present the design of an innovative molecular neuroprotective strategy and provide proof-of-concept for its implementation, relying on the injury-mediated activation of an ectopic gene construct. As oxidative injury leads to the intracellular liberation of zinc, we hypothesize that tapping onto the zinc-activated metal regulatory element ( MRE ) transcription factor 1 system to drive expression of the Kv2.1-targeted hepatitis C protein NS5A (hepatitis C nonstructural protein 5A) will provide neuroprotection by preventing cell death-enabling cellular potassium loss in rat cortical neurons in vitro. Indeed, using biochemical and morphologic assays, we demonstrate rapid expression of MRE -driven products in neurons. Further, we report that MRE -driven NS5A expression, induced by a slowly evolving excitotoxic stimulus, functionally blocks injurious, enhanced Kv2.1 potassium whole-cell currents and improves neuronal viability. We suggest this form of "on-demand" neuroprotection could provide the basis for a tenable therapeutic strategy to prevent neuronal cell death in neurodegeneration., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Hypoxic-ischemic encephalopathy (HIE) refers to acute brain injury that results from perinatal asphyxia. HIE is a major cause of neonatal seizures, and outcomes can range from apparent recovery to severe cognitive impairment, cerebral palsy, and epilepsy. Acute partial seizures frequently aid in indicating the severity and localization of brain injury. However, evidence also suggests that the occurrence of seizures further increases the likelihood of epilepsy in later life regardless of the severity of the initial injury. Here, we describe a neonatal rat model of seizure-provoking mild hypoxia without overt brain injury that has been used to investigate potential epileptogenic effects of hypoxia-associated seizures alone on neonatal brain development. Clinically, HIE is defined by brain injury, and thus, this model is not intended to mimic clinical HIE. Rather, its utility is in providing a model to understand the dynamic and long-term regulation of brain function and how this can be perturbed by early life seizures that are provoked by a commonly encountered pathophysiological trigger. Additionally, the model allows the study of brain pathophysiology without the potential confound of variable neuroanatomical changes that are reactive to widespread cell death.

As the predominant mediator of the delayed rectifier current, K V 2.1 is an important regulator of neuronal excitability. K V 2.1, however, also plays a well-established role in apoptotic cell death. Apoptogenic stimuli induce syntaxin-dependent trafficking of K V 2.1, resulting in an augmented delayed rectifier current that acts as a conduit for K + efflux required for pro-apoptotic protease/nuclease activation. Recent evidence suggests that K V 2.1 somato-dendritic clusters regulate the formation of endoplasmic reticulum-plasma membrane junctions that function as scaffolding sites for plasma membrane trafficking of ion channels, including K V 2.1. However, it is unknown whether K V 2.1 somato-dendritic clusters are required for apoptogenic trafficking of K V 2.1. By overexpression of a protein derived from the C-terminus of the cognate channel K V 2.2 (K V 2.2CT), we induced calcineurin-independent disruption of K V 2.1 somato-dendritic clusters in rat cortical neurons, without altering the electrophysiological properties of the channel. We observed that K V 2.2CT-expressing neurons are less susceptible to oxidative stress-induced cell death. Critically, expression of K V 2.2CT effectively blocked the increased current density of the delayed rectifier current associated with oxidative injury, supporting a vital role of K V 2.1-somato-dendritic clusters in apoptogenic increases in K V 2.1-mediated currents., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Key Points: Increases in intracellular Zn(2+) concentrations are an early, necessary signal for the modulation of Kv2.1 K(+) channel localization and physiological function. Intracellular Zn(2+) -mediated Kv2.1 channel modulation is dependent on calcineurin, a Ca(2+) -activated phosphatase. We show that intracellular Zn(2+) induces a significant increase in ryanodine receptor-dependent cytosolic Ca(2+) transients, which leads to a calcineurin-dependent redistribution of Kv2.1 channels from pre-existing membrane clusters to diffuse localization. As such, the link between Zn(2+) and Ca(2+) signalling in this Kv2.1 modulatory pathway is established. We observe that a sublethal ischaemic preconditioning insult also leads to Kv2.1 redistribution in a ryanodine receptor-dependent fashion. We suggest that Zn(2+) may be an early and ubiquitous signalling molecule mediating Ca(2+) release from the cortical endoplasmic reticulum via ryanodine receptor activation., Abstract: Sublethal injurious stimuli in neurons induce transient increases in free intracellular Zn(2+) that are associated with regulating adaptive responses to subsequent lethal injury, including alterations in the function and localization of the delayed-rectifier potassium channel, Kv2.1. However, the link between intracellular Zn(2+) signalling and the observed changes in Kv2.1 remain undefined. In the present study, utilizing exogenous Zn(2+) treatment, along with a selective Zn(2+) ionophore, we show that transient elevations in intracellular Zn(2+) concentrations are sufficient to induce calcineurin-dependent Kv2.1 channel dispersal in rat cortical neurons in vitro, which is accompanied by a relatively small but significant hyperpolarizing shift in the voltage-gated activation kinetics of the channel. Critically, using a molecularly encoded calcium sensor, we found that the calcineurin-dependent changes in Kv2.1 probably occur as a result of Zn(2+) -induced cytosolic Ca(2+) release via activation of neuronal ryanodine receptors. Finally, we couple this mechanism with an established model for in vitro ischaemic preconditioning and show that Kv2.1 channel modulation in this process is also ryanodine receptor-sensitive. Our results strongly suggest that intracellular Zn(2+) -initiated signalling may represent an early and possibly widespread component of Ca(2+) -dependent processes in neurons., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Purpose: Cerebral hypoxia is a major cause of neonatal seizures, and can lead to epilepsy. Pathologic anatomic and physiologic changes in the dentate gyrus have been associated with epileptogenesis in many experimental models, as this region is widely believed to gate the propagation of limbic seizures. However, the consequences of hypoxia-induced seizures for the immature dentate gyrus have not been extensively examined., Methods: Seizures were induced by global hypoxia (5-7% O2 for 15 min) in rat pups on postnatal day 10. Whole-cell voltage-clamp recordings were used to examine A-type potassium currents (IA ) in dentate granule cells in hippocampal slices obtained 1-17 days after hypoxia treatment., Key Findings: Seizure-inducing hypoxia resulted in decreased maximum IA amplitude in dentate granule cells recorded within the first week but not at later times after hypoxia treatment. The decreased IA amplitude was not associated with changes in the voltage-dependence of activation or inactivation removal, or in sensitivity to inhibition by 4-aminopyridine (4-AP). However, consistent with the role of IA in shaping firing patterns, we observed in the hypoxia group a significantly decreased latency to first spike with depolarizing current injection from hyperpolarized potentials. These differences were not associated with changes in resting membrane potential or input resistance, and were eliminated by application of 10 m 4-AP., Significance: Given the role of IA to slow action potential firing, decreased IA could contribute to long-term hippocampal pathology after neonatal seizure-inducing hypoxia by increasing dentate granule cell excitability during a critical window of activity-dependent hippocampal maturation., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

The H-current (I(H)) regulates membrane electrical activity in many excitable cells. The antiepileptic drug gabapentin (GBP) has been shown to increase I(H) in hippocampal area CA1 pyramidal neurons, and this has been proposed as an anticonvulsant mechanism of action. I(H) also regulates excitability in some types of hippocampal interneuron that provide synaptic inhibition to CA1 pyramidal neurons, suggesting that global pharmacological I(H) enhancement could have more complex effects on the local synaptic network. However, whether I(H) in CA1 interneurons is modulated by GBP has not been examined. In this study, we tested the effects of GBP on I(H) on hippocampal area CA1 stratum oriens non-pyramidal neurons, and on spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in immature rat brain slices. GBP (100μM) increased I(H) in approximately 67% of interneurons that exhibited I(H), with no apparent effect on cell types that did not exhibit I(H). GBP also increased the frequency of spontaneous (but not miniature) inhibitory postsynaptic currents in pyramidal neurons without altering amplitudes or rise and decay times. These data indicate that I(H) in a subset of CA1 interneuron types can be increased by GBP, similarly to its effect on I(H) in pyramidal neurons, and further, that indirectly increased spontaneous inhibition of pyramidal neurons could contribute to its anticonvulsant effects., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The hyperpolarization-activated cation current (I(H)) regulates the electrical activity of many excitable cells, but its precise function varies across cell types. The antiepileptic drug lamotrigine (LTG) was recently shown to enhance I(H) in hippocampal CA1 pyramidal neurons, showing a potential anticonvulsant mechanism, as I(H) can dampen dendrito-somatic propagation of excitatory postsynaptic potentials in these cells. However, I(H) is also expressed in many hippocampal interneurons that provide synaptic inhibition to CA1 pyramidal neurons, and thus, I(H) modulation may indirectly regulate the inhibitory control of principal cells by direct modulation of interneuron activity. Whether I(H) in hippocampal interneurons is sensitive to modulation by LTG, and the manner by which this may affect the synaptic inhibition of pyramidal cells has not been investigated. In this study, we examined the effects of LTG on I(H) and spontaneous firing of area CA1 stratum oriens interneurons, as well as on spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons in immature rat brain slices. LTG (100 microM) significantly increased I(H) in the majority of interneurons, and depolarized interneurons from rest, promoting spontaneous firing. LTG also caused an increase in the frequency of spontaneous (but not miniature) IPSCs in pyramidal neurons without significantly altering amplitudes or rise and decay times. These data indicate that I(H) in CA1 interneurons can be increased by LTG, similarly to I(H) in pyramidal neurons, that I(H) enhancement increases interneuron excitability, and that these effects are associated with increased basal synaptic inhibition of CA1 pyramidal neurons.

Hypoxia is the most common cause of neonatal seizures and can lead to epilepsy, but the epileptogenic mechanisms are not yet understood. We have previously shown that hypoxia-induced seizures in the neonatal rat result in acutely decreased amplitudes and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in hippocampal CA1 pyramidal neurons. In the current study, we asked whether such changes persist for several days following hypoxia-induced seizures. Similar to the acute findings, we observed decreased frequency and amplitudes of sIPSCs and decreased mIPSC amplitudes in CA1 pyramidal neurons at 3-5 days after hypoxia. However, in contrast to the acute findings, we observed no differences between hypoxia-treated and control groups in mIPSC frequency. Additionally, by 7 days after hypoxia, sIPSC amplitudes in the hypoxia group had recovered to control levels, but sIPSC frequency remained decreased. These data indicate that the persistently decreased sIPSC frequency result from decreased firing of presynaptic inhibitory interneurons, with only transient possible changes in postsynaptic responses to GABA release.