The present disclosure relates generally to the field of pharmaceuticals. Specifically, the present disclosure is directed to a composition for inhibition of IRE1 for management of epilepsy comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. [0003] Epilepsy is a chronic neurologic disorder that may be a risk for progressive damage to involved brain structures such as the hippocampus promoting cognitive dysfunction (Saniya K, Patil BG, Chavan MD, Prakash KG, Sailesh KS, Archana R, Johny M. Neuroanatomical changes in brain structures related to cognition in epilepsy: an update. Journal of natural science, biology, and medicine. 2017 Jul; 8(2): 139). Neuronal death has been considered to be a present issue clinically observed with mortality in patients with temporal lobe epilepsy and status epilepticus. The sudden unexplained death is likely to be expected with epileptic patients due to uncontrolled seizures leading to brain damage seen in the temporal lobe and status epilepticus (Dingledine R, Varvel NH, Dudek FE. When and how do seizures kill neurons, and is cell death relevant to epileptogenesis?. Inlssues in clinical epileptology: a view from the bench 2014, 109-122). The numerous mechanisms are associative with prolonged epileptic seizures causing neuronal injury resulting in inflammatory responses and production of reactive oxygen species involved in neuronal cell death (Brodie MJ. Antiepileptic drug therapy the story so far. Seizure. 2010, 19(10), 650-5, and Guimaraes J, Ribeiro JA. Pharmacology of antiepileptic drugs in clinical practice. The neurologist. 2010, 16(6), 353-7). These include the elevation of intracellular calcium, sodium ions channel influx, accumulation of oxidizing free radicals, various inflammatory mediators, impairment of mitochondrial function, activation of apoptotic and

autophagic programs, excessive activation of ionotropic receptors resulting in hyper depolarization of membrane potential leading to excitotoxicity (Thiffault I, Speca DJ, Austin DC, Cobb MM, Eum KS, Safina NP, Grote L, Farrow EG, Miller N, Soden S, Kingsmore SF. A novel epileptic encephalopathy mutation in KCNBl disrupts Kv2. 1 ion selectivity, expression, and localization. Journal of General Physiology. 2015,146(5), 399-410, Sugiura Y, Ugawa Y. Epilepsy and ion channels. Rinsho shinkeigaku= Clinical neurology. 2016, 57(1), 1-8, and McElroy PB, Liang LP, Day BJ, Patel M. Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Experimental neurology. 2017, 298, 13-22). The involvement of certain apoptotic processes (i.e., apoptosis, autophagy, phagocytosis, and necroptosis) is also seen amongst the exotoxin event of brain insult induced by repetitive seizures causing neurodegeneration (Henshall DC, Simon RP. Epilepsy and apoptosis pathways. Journal of Cerebral Blood Flow & Metabolism. 2005, 25(12), 1557-72). Disruption of intracellular endoplasmic reticulum and mitochondria organelle is a key feature of neuronal death in epilepsy and has a role in triggering apoptosis and activation of pro-apoptotic Bax/Bak recognized by mitochondrial outer membrane permeabilization further leading to DNA fragmentation (Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO reports. 2006, 7(9), 880-5, Rasheva VI, Domingos PM. Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis. 2009, 14(8), 996-1007, and Yamamoto A, Murphy N, Schindler CK, So NK, Stohr S, Taki W, Prehn JH, Henshall DC. Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy. Journal of Neuropathology & Experimental Neurology. 2006, 65(3), 217-25). The enhanced levels of reactive oxygen species, inflammatory mediators, pro-apoptotic proteins (BH3-only proteins), and caspases implications are the features of disruption of endoplasmic reticulum and mitochondrial dysfunction associated neuronal apoptotic death in epilepsy (Chen G, Gong M, Yan M, Zhang X. Sevqflurane induces endoplasmic reticulum stress mediated apoptosis in hippocampal neurons of aging rats. PLoS One. 2013, 8(2), e57870, and Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M. Apoptosis

induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neuroscience letters. 2004, 357(2), 127-30).
[0004] The activation of the inositol-requiring enzyme (IREl) as an initiator of recruiting tumor necrosis factor receptor (TNFR)-associated factor-2 (TRAF2), apoptosis-signalling-kinase 1 (ASK1) cascades, and increasing Bim protein (pro-apoptotic protein) represents mitochondrial dysfunction mediated neuronal apoptotic death. ER stress mediates the apoptotic pathway by the interaction of IREl with Bax which further releases the cytochrome C (Cyt C) into the cytosol that indicates that the endoplasmic reticulum stress enhances the mitochondrial dysfunction induced apoptosis. (Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neuroscience letters. 2004, 357(2), 127-30, Malhotra JD, Kaufman RJ. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harbor perspectives in biology. 2011, 3(9), a004424, Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. The Journal of clinical investigation. 2005, 115(10), 2656-64, and Li J, Zhang D, Brundel BJ, Wiersma M. Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?. Cells. 2019, 8(12), 1617).
[0005] The inventors of the present disclosure provide a composition comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde for the selective inhibition of inositol-requiring enzyme (IREl) for neuroprotective effect.
OBJECTS OF THE INVENTION
[0006] An object of the present disclosure is to provide a composition for
inhibition of IREl for treatment, prevention or amelioration of epilepsy.
[0007] Another object of the present disclosure is to provide a composition for
attenuating kindling seizures induced by pentylenetetrazole (PTZ).
[0008] Yet another object of the present disclosure is to provide a composition for
attenuating spontaneous seizures induced by pilocarpine.

SUMMARY OF THE INVENTION
[0009] This summary is provided to introduce a selection of concepts in a
simplified form that are further described below in Detailed Description section.
This summary is not intended to identify key features or essential features of the
claimed subject matter, nor is it intended to be used as an aid in determining the
scope of the claimed subject matter.
[0010] In an aspect, the present disclosure provides a composition for inhibition
of IREl for management of epilepsy comprising 7-Hydroxy-4-methyl-2-oxo-2H-
chromene-8-carbaldehyde.
[0011] In an embodiment, the present disclosure provides a composition for
inhibition of IREl for management of PTZ induced kindled seizures comprising
7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde. In an embodiment, the
present disclosure provides a composition for inhibition of IREl for management
of pilocarpine induced spontaneous recurrent seizures comprising 7-Hydroxy-4-
methyl-2-oxo-2H-chromene-8-carb aldehyde.
[0012] In an embodiment, the present disclosure provides a composition for
inhibition of IREl for management of epilepsy comprising 7-Hydroxy-4-methyl-
2-oxo-2H-chromene-8-carbaldehyde and a pharmaceutically acceptable excipient.
[0013] In yet another aspect, the present disclosure provides use of a composition
comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde, for the
inhibition of IREl for management of epilepsy.
[0014] In still another aspect, the present disclosure provides a method of
inhibition of IREl for management of epilepsy by administering to a subject in
need thereof, a therapeutically effective amount of a composition comprising 7-
Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde.
[0015] These and other features, aspects, and advantages of the present subject
matter will be better understood with reference to the following description and
appended claims.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0016] The following drawings form part of the present specification and are
included to further illustrate aspects of the present disclosure. The disclosure may
be better understood by reference to the drawings in combination with the detailed
description of the specific embodiments presented herein.
Figure 1 provides the statistical analysis of the effect of 7-Hydroxy-4-methyl-2-
oxo-2H-chromene-8-carbaldehyde on PTZ-induced kindled seizures in mice, as
per an embodiment of the present disclosure. Values are expressed as Mean ±
SEM, a=P<0.05 vs Vehicle Control; b=P<0.05 vs PTZ Control.
Figure 2 provides the statistical analysis of the effect of 7-Hydroxy-4-methyl-2-
oxo-2H-chromene-8-carbaldehyde on PC-induced kindled seizures in mice, as per
an embodiment of the present disclosure. Values are expressed as Mean ± SEM,
a=P<0.05 vs Vehicle Control; b=P<0.05 vs PC Control.
Figure 3 provides the statistical analysis of the effect of IRE-1 inhibitor pre-
treatment on IL-ip concentrations in PTZ-induced kindling model, in mice, as per
an embodiment of the present disclosure. Values are expressed as Mean ± SEM,
a=P<0.05 vs Vehicle Control; b=P<0.05 vs PTZ Control.
Figure 4 provides the statistical analysis of the effect of IRE-1 inhibitor pre-
treatment on TNF-a concentrations in PTZ-induced kindling model, in mice, as
per an embodiment of the present disclosure. Values are expressed as Mean ±
SEM, a=P<0.05 vs Vehicle Control; b=P<0.05 vs PTZ Control.
Figure 5 provides the statistical analysis of the effect of IRE-1 inhibitor pre-
treatment on NF-KB concentrations in PTZ-induced kindling model, in mice, as
per an embodiment of the present disclosure. Values are expressed as Mean ±
SEM, a=P<0.05 vs Vehicle Control; b=P<0.05 vs PTZ Control.
Figure 6 provides the statistical analysis of the effect of IRE-1 inhibitor pre-
treatment on IL-ip concentrations in PC-induced kindling model, in mice, as per
an embodiment of the present disclosure. Values are expressed as Mean ± SEM,
a=P<0.05 vs Vehicle Control; b=P<0.05 vs PC Control.
Figure 7 provides the statistical analysis of the effect of IRE-1 inhibitor pre-
treatment on TNF-a concentrations in PC-induced kindling model, in mice, as per

an embodiment of the present disclosure. Values are expressed as Mean ± SEM, a=P<0.05 vs Vehicle Control; b=P<0.05 vs PC Control.
Figure 8 provides the statistical analysis of the effect of IRE-1 inhibitor pre-treatment on NF-KB concentrations in PC-induced kindling model, in mice, as per an embodiment of the present disclosure. Values are expressed as Mean ± SEM, a=P<0.05 vs Vehicle Control; b=P<0.05 vs PC Control.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0018] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. [0019] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0020] In some embodiments, numbers have been used for quantifying weights, percentages, dosages, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the

term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [0021] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0022] As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. [0023] Unless the context requires otherwise, throughout the specification which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."
[0024] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. [0025] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate

the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. [0026] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0027] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0028] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention. [0029] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments. [0030] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0031] The term 'therapeutically effective amount' generally refers to the amount
that when administered to a subject is sufficient to affect the treatment intended by
the drug.
[0032] The term, "pharmaceutically acceptable" as used herein refers to an
excipient comprised of a material that is not biologically or otherwise undesirable.
[0033] The term, "subject" as used herein refers to an animal, preferably a
mammal, and most preferably a human. The term "mammal" used herein refers to
warm-blooded vertebrate animals of the class 'mammalia' , including humans,
characterized by a covering of hair on the skin and, in the female, milk-producing
mammary glands for nourishing the young, the term mammal includes animals
such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0034] The term 'management' refers to treatment, amelioration and/or
prevention of the condition. Management of epilepsy includes the control of
epileptic seizures, generalized seizures, and status epilepticus.
[0035] In an embodiment, the present disclosure provides a composition for
inhibition of IREl for management of epilepsy comprising 7-Hydroxy-4-methyl-
2-oxo-2H-chromene-8-carbaldehyde.
[0036] In an embodiment, 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde includes pharmaceutically acceptable salts thereof.
[0037] In an embodiment, the epilepsy is induced by pentylenetetrazol (PTZ). In
an embodiment, the composition attenuates kindling seizures induced by
pentylenetetrazole (PTZ). In an embodiment, the composition attenuates kindling
seizures induced by pentylenetetrazole (PTZ) for generalized tonic or clonic
seizures. In an embodiment, the epilepsy is induced by pilocarpine. In an
embodiment, the composition attenuates spontaneous seizures induced by
pilocarpine. In an embodiment, the composition attenuates spontaneous seizures
induced by pilocarpine for status epileticus.
[0038] In an embodiment, the present disclosure provides a composition for
inhibition of IREl for management of PTZ induced kindled seizures comprising
7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde. In an embodiment, the
present disclosure provides a composition for inhibition of IREl for management

of pilocarpine induced spontaneous recurrent seizures comprising 7-Hydroxy-4-
methyl-2-oxo-2H-chromene-8-carb aldehyde.
[0039] In an embodiment, the composition may be in the form of a medicament.
The medicament or composition may be administered to a subject along with
alternative treatment methods for epilepsy.
[0040] Without being bound by theory, it is believed that IREl initiates apoptotic
signalling as an adaptive mechanism under the chronic seizures inducing
endoplasmic reticulum stress, enhancing mitochondrial dysfunction mediating
apoptotic death participating in pathogenesis of epilepsy. 7-Hydroxy-4-methyl-2-
oxo-2H-chromene-8-carbaldehyde, a selective inhibitor of IREl, provides a
protective effect on the development of PTZ induced kindled seizures and
pilocarpine induced spontaneous recurrent seizures in mice.
[0041] In an embodiment, the composition may be administered in a
therapeutically effective amount to a subject. The therapeutically effective amount
may be determined based on the patient history, body weight and severity of the
condition.
[0042] In an embodiment, the present disclosure provides a composition for
inhibition of IREl for management of epilepsy comprising 7-Hydroxy-4-methyl-
2-oxo-2H-chromene-8-carbaldehyde and a pharmaceutically acceptable excipient.
[0043] In an embodiment, the present disclosure provides a formulation for
inhibition of IREl for management of epilepsy comprising 7-Hydroxy-4-methyl-
2-oxo-2H-chromene-8-carbaldehyde and a pharmaceutically acceptable excipient.
[0044] In an embodiment, the excipient may be selected from those well-known
in the art. The excipient may be selected from carrier, dispersants, binders,
buffering agents, preservatives, stabilizers, emulsifiers, surfactants, colouring
agents, flavouring agents, sugars, diluents, or combinations thereof.
[0045] In an embodiment, the pharmaceutically acceptable excipient may include
but is not limited to mannitol, sorbitol, sucrose, microcrystalline cellulose,
phospholipids, fatty acids, metals of fatty acids, cellulosic derivatives,
polyacrylates, povidones, polyvinylpyrrolidone, starch, magnesium stearate,
microcrystalline cellulose, colloidal silicon dioxide, precipitated silicon dioxide,

sodium bicarbonate, sodium citrate, croscarmellose sodium, crospovidone,
sodium starch glyconate, stearates, talc, kaolin, calcium carbonate, dextrates,
carbopol, carbomer, lecithin, sodium chloride, gelatine, sodium acrylate, EDTA,
sodium gluconate, glycerine, potassium sorbate, ethanol, polyol, water, saline and
dimethyl sulfoxide.
[0046] In an embodiment, the formulation may preferably be administered in a
dose range of about 1 mg/kg to about 500 mg/kg of body weight each day, more
preferably in the range of about 1 mg/kg to about 50 mg/kg of body weight each
day. The dosage may be single dosage or several dosages divided in the day.
[0047] In an embodiment, the formulation may be administered orally,
intracerebrally, transdermally, subcutaneously, sublingually, intra-nasally,
intravenously, intraperitoneally, rectally, buccal or intramuscularly. Preferably,
the composition may be administered orally or intraperitoneally.
[0048] The formulation may be administered in any form known in the art and
suitable for patient compliance including pills, tablets, capsules, lozenges,
powders, granules, patches, suspensions, dispersions, solutions, microparticles,
nanoparticles, aerosols, or sustained release particles. In an embodiment, the
formulation may be delivered via injection or infusion.
[0049] In yet another embodiment, the present disclosure provides use of a
composition comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde, for inhibition of IRE1 for management of epilepsy.
[0050] In still another embodiment, the present disclosure provides a method of
inhibition of IRE1 for management of epilepsy by administering to a subject in
need thereof, a therapeutically effective amount of a composition or formulation
comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde.
[0051] The therapeutically effective amount maybe determined based on the
patient history, body weight and severity of the condition.
[0052] The management of epilepsy includes the decrease in IL-ip concentration,
TNF-a concentration and NFK-P concentration.
[0053] While the foregoing describes various embodiments of the disclosure,
other and further embodiments of the disclosure may be devised without departing

from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art. EXAMPLES
[0054] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. MATERIAL AND METHODS: Experimental Animals
[0055] Male Swiss albino mice, weighing 25±2g maintained on a standard laboratory diet (Ashirwad Pvt. Ltd., Chandigarh, India) having free access to tap water, were employed in the present study. They were housed in the departmental animal house and were exposed to 12 hr cycle of light and dark. The experiments were conducted in a semi-sound proof laboratory. The experimental protocols were approved by the institutional animal ethics committee. Care of the experimental animals was carried out as per the guidelines of the Committee for Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Government of India. Drug and Chemicals
[0056] The chemicals and drugs were procured from standard suppliers and were of analytical grade. Pentylenetetrazol (Sigma, St. Louis, USA), 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-Carbaldehyde (Sigma, St. Louis, USA),

pilocarpine nitrate (FDC Limited, Aurangabad, India) and diazepam (Jackson
Laboratories Pvt. Ltd., Amritsar, India), hyoscine butyl bromide (German
Remedies Ltd., Mumbai, India) were dissolved in normal saline (which served as
a vehicle for preparing all the drug solutions/dilutions). All drug solutions were
freshly prepared before use.
7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde was solubilised in 10%
DMSO for administration.
EXAMPLE 1: Induction of the pentylenetetrazole kindled model of epilepsy
in mice
Pentylenetetrazole induced kindled seizure severity score assessment protocol
Group I (Vehicle control group-a): vehicle (10 ml kg"1, i.p.) every alternate day
for 15 days + vehicle (10 ml kg"1 d"1, i.p.) for 16 days (day 0 to day 15).
Group II (Pentylenetetrazole (PTZ) control group): PTZ (40 mg kg"1, i.p.) every
alternate day for 15 days + vehicle (10 ml kg"1 d"1, i.p.) for 16 days (day 0 to day
15).
Group III (Low dose (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde)
(5 mg/kg (i.p) + PTZ group): PTZ (40 mg kg"1, i.p.) every alternate day for 15
days + (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde) (5 mg/kg (i.p)
for 16 days (day 0 to day 15).
Group IV (High dose (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde)
(10 mg/kg (i.p) + PTZ group): PTZ (40 mg kg"1, i.p.) every alternate day for 15
days + (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde) (10 mg/kg
(i.p) for 16 days (day 0 to day 15).
[0057] Pentylenetetrazole (PTZ) was administered in a sub-convulsant dose (40
mg/kg, i.p.) on alternate days for a total period of 15 days. The severity of kindled
seizures was assessed in terms of a composite kindled seizure severity score
(KSSS). Drug treatment was continued throughout the experimental procedure
(once daily from day 0 to day 15 i.e. 16 days). KSSS quantification was
performed 4 hrs before the drug administration on the behavioral assessment day
(every alternate day until day 15). Results are presented in Figure 1.

EXAMPLE 2: Induction of the status epilepticus provoked spontaneous recurrent seizure activity in mice
Pilocarpine induced spontaneous recurrent seizure severity score assessment
protocol
Group I (vehicle control group-b): vehicle (10 ml kg"1 d"1, i.p.) for the 31 days
starting 6th day after SE + vehicle (10 ml kg"1, i.p. every 20 min until the
completion of 80 min period followed by diazepam (3 mg kg"1, i.p.) 40 min after
the last injection) on day 1.
Group II (pilocarpine (PC) control group): vehicle (10 ml kg"1 d"1, i.p.) for the 31
days starting 6th day after SE + PC (100 mg kg"1, i.p. every 20 min until the onset
of SE followed by diazepam (3 mg kg"1, i.p.) 40 min after SE) on day 1.
Group III (low dose (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde)
(5 mg/kg (i.p) + PC group): (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde) (5 mg/kg (i.p) for the 31 days period starting 6th day after SE + PC
(100 mg kg"1, i.p. every 20 min until the onset of SE followed by diazepam (3 mg
kg"1, i.p.) 40 min after SE) on day 1.
Group IV (high dose (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde)
10 mg/kg (i.p) + PC group): (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde) (10 mg/kg (i.p) for the 31 days period starting 6th day after SE +
PC (100 mg kg"1, i.p. every 20 min until the onset of SE followed by diazepam (3
mg kg"1, i.p.) 40 min after SE) on day 1.
[0058] Intraperitoneal application of pilocarpine (100 mg/ kg, i.p.) was repeated
every 20 min until the onset of status epilepticus. A spontaneous recurrent seizure
severity score (SRSSS) was recorded as a measure of the quantitative assessment
of progressive development of spontaneous recurrent seizures induced after
pilocarpine status epilepticus (SE). Drug treatment was started 6 days after the SE
episode and was continued until day 37 (dosing was started 1 day prior to the first
behavioural assessment day). Behavioural assessment was performed prior to the
drug administration (every third day until day 37). Results are presented in Figure
2.

[0059] The neuroprotective effect of 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde, a selective inhibitor of inositol-requiring enzyme, produced at a high dose of 10 mg/kg; (i.p.) and 5 mg/kg; (i.p.) on the development of chemically induced kindled PTZ and Pilocarpine induced seizures in the laboratory animals was studied. The high dose of 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-Carbaldehyde (10 mg/kg), i.p showed to be effective in attenuating the development of PTZ induced kindling severity scoring and pilocarpine-(PC)-status-epilepticus-induced spontaneous recurrent seizures scoring in mice i.e., the Group IV (High dose (7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde) + PTZ & PC as compared to the disease groups Group II (Pentylenetetrazole (PTZ)/ control group) & Group II (pilocarpine (PC)/control group). Thus, the inositol-requiring enzyme (IRE1) plays a potential role in causing neuronal death in epilepsy.
EXAMPLE 3: Estimation of Oxidative stress
[0060] Estimation of inflammatory mediators - TNF-a, NF-KB and IL-ip in brain were done in Pilocarpine induced kindling model and PTZ induced kindling model with the help and instructions provided by Krishgen Biosystems Elisa kit. Results are presented in Figures 3-8.
[0061] In response to the ER stress, there is an activation of tumor necrosis factor receptor (TNFR)-associated factor-2 (TRAF2) which also represents the downstream signaling of activating transcriptional factor NF-kB increasing the pro-inflammatory mediators like cytokines (IL-ip, NF-kB, and TNF-a) provoking neuronal death in epilepsy. The ELISA results showed the decreased levels of inflammatory mediators in rodents receiving treatment of 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde at a dose of 10 mg/kg; (i.p.) in both PTZ and pilocarpine-induced seizures compared with disease groups Group II (Pentylenetetrazole (PTZ)/ control group) & Group II (pilocarpine (PC)/control group).

ADVANTAGES OF THE INVENTION
[0062] The present disclosure provides a composition for treatment, prevention or
amelioration of epilepsy.
[0063] The present disclosure provides a composition for attenuating kindling
seizures induced by pentylenetetrazole (PTZ) and spontaneous seizures induced
by pilocarpine.
[0064] The present disclosure provides a composition that increases catalase
activity and decreases TBARS activity and glutathione activity.
[0065] The present disclosure provides a composition that decreases IL-ip
concentration, TNF-a concentration and NFK-P concentration.

We Claim:
1. A composition for inhibition of IRE1 for management of epilepsy comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde.
2. The composition as claimed in claim 1, wherein 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde includes pharmaceutically acceptable salts thereof.
3. The composition as claimed in claim 1, wherein the epilepsy is induced by pentylenetetrazole (PTZ).
4. The composition as claimed in claim 1, wherein the epilepsy is induced by pilocarpine.
5. The composition as claimed in claim 1, wherein the composition is in the form of a medicament.
6. The composition as claimed in claim 1, wherein further comprises a
pharmaceutically acceptable excipient.
7. A formulation for inhibition of IRE1 for management of epilepsy comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde and a pharmaceutically acceptable excipient.
8. The formulation as claimed in claim 7, wherein the excipient is selected from carrier, dispersants, binders, buffering agents, preservatives, stabilizers, emulsifiers, surfactants, colouring agents, flavouring agents, sugars, diluents, or combinations thereof.
9. The formulation as claimed in claim 7, wherein the formulation is administered in a dose range of 1 mg/kg to 500 mg/kg of body weight each day.

10. The formulation as claimed in claim 7, wherein the formulation is administered orally, intracerebrally, transdermally, subcutaneously, sublingually, intra-nasally, intravenously, intraperitoneally, rectally, buccal or intramuscularly.
11. The formulation as claimed in claim 7, wherein the formulation is administered as pills, tablets, capsules, lozenges, powders, granules, patches, suspensions, dispersions, solutions, microparticles, nanoparticles, aerosols, or sustained release particles.

12. A method of inhibition of IREl for management of epilepsy by administering
to a subject in need thereof, a therapeutically effective amount of a composition or
formulation comprising 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde.