FIELD OF THE INVENTION

The present invention discloses novel synergistic nutritional compositions for treating seizures and chronic inflammatory diseases. Particularly, the invention relates to potent synergistic nutritional composition comprising exogenous combination of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists and nuclear factor erythroid 2-related factor 2 (NRF2) activators present in suitable weight ratio, along with pharmaceutically acceptable recipients. More particularly, the invention provides potent synergistic nutritional composition comprising exogenous combination of tridecanoin and L-ergothioneine present in suitable weight ratio, along with pharmaceutically acceptable recipients.

BACKGROUND OF THE INVENTION

Seizure disorder relates to any condition in which seizures may be a symptom. Seizure disorder is often used in place of the term “epilepsy”. A general definition for the word “seizure” is a period of abnormal, synchronous excitation of a neuronal population. Seizures typically last for seconds or minutes but can be prolonged and continuous in the case of status epilepticus. A seizure refers to a single surge of electrical activity in a person's brain. A seizure disorder is a condition in which a person has multiple seizures. The tendency to have recurrent seizures leads to epilepsy. Moreover, epilepsy is a neurological condition characterized by two or more unprovoked seizures.

Anything that interrupts the normal connections between nerve cells in the brain can cause a seizure. This includes a high fever, low blood sugar, high blood sugar, alcohol or drug withdrawal, or a brain concussion. Under these circumstances, anyone can have one or more seizures. However, when a person has two or more recurrent, unprovoked seizures, he or she is considered to have epilepsy. There are many possible causes of epilepsy, including an imbalance of nerve-signaling chemicals called neurotransmitters, tumors, strokes, and brain damage from illness or injury, or some combination of these.

A seizure occurs when part(s) of the brain receives a burst of abnormal electrical signals that temporarily interrupts normal electrical brain function. It is a sudden, uncontrolled electrical disturbance in the brain. It can cause changes in human behavior, movements or feelings, and in levels of consciousness.

The type of seizure depends on which part of the brain and how much of the brain is affected and what happens during the seizure. The two broad categories of epileptic seizures are generalized (absence, atonic, tonic-clonic, myoclonic) seizures and partial (simple and complex) seizures.

The term “seizure” is often used interchangeably with “convulsion”. During convulsions a person has uncontrollable shaking that is rapid and rhythmic, with the muscles contracting and relaxing repeatedly. A seizure, formally known as an epileptic seizure, is a period of symptoms due to abnormally excessive or contemporaneous neuronal activity in the brain. Most of the time these episodes last less than 2 minutes and it takes some time to return to normal.

A profusion of new antiepileptic drugs (AEDs) has appeared in the past 5 years. It is further needed to understand how normal neuronal function goes awry in epilepsy, particularly normal synaptic transmission and neuronal firing, and the mechanisms by which AEDs control the hyperexcitability that underlies epilepsy.

According to the World Health Organization report, epilepsy accounts for a significant proportion of the world's disease burden, affecting around 50 million people worldwide. The estimated proportion of the general population with active epilepsy (i.e., continuing seizures or with the need for treatment) at a given time is between 4 and 10 per 1000 people. Globally, an estimated five million people are diagnosed with epilepsy each year. In high-income countries, there are estimated to be 49 per 100,000 people diagnosed with epilepsy each year. In low- and middle-income countries, this figure can be as high as 139 per 100,000 people. Nearly 80% of people with epilepsy live in low- and middle-income countries. Almost 3 million Americans live with epilepsy.

Epilepsy is not contagious. Although many underlying disease mechanisms can lead to epilepsy, the cause of the disease is still unknown in about 50% of the cases globally. The causes of epilepsy are divided into the following categories: structural, genetic, infectious, metabolic, immune, which include brain damage from prenatal or perinatal; congenital abnormalities or genetic conditions with associated brain malformations; severe head injury; ischemic stroke; an infection of the brain such as meningitis, encephalitis or neurocysticercosis, certain genetic syndromes; and a brain tumour.

Genetic mutations may play a key role in the development of certain epilepsies. Many types of epilepsy affect multiple blood-related family members, directing to a strong inherited genetic component. In other cases, gene mutations may occur spontaneously and contribute to development of epilepsy in people with no family history of the disorder (called “de novo” mutations). Overall, researchers estimate that hundreds of genes could play a role in the seizure disorders.

The American Association of Neurological Surgeons have reported that epilepsy affects more than 300,000 children under the age of 15, and more than 90,000 young people in this group have seizures that cannot be adequately treated. The onset rate starts to increase when individuals age, particularly as they develop strokes, brain tumors or Alzheimer's disease, all of which may cause epilepsy. Reports indicate that more than 570,000 adults over the age of 65 suffer from the disorder.

Epilepsy, a disorder that affects 1% of the population worldwide, is classically thought to arise from an imbalance between excitation and inhibition in a localized region, multiple brain areas or the whole brain. Long-term changes in presynaptic morphology and synaptic vesicle recycling have been described in the animal models of epilepsy. These changes include alterations in the morphology of mossy fiber synaptic buttons, including increased size, number of release sites, and number of vesicles in the reserve pool and the readily releasable pool.

Synaptic transmission is regulated by diverse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors and signaling, and modulators of neurotransmission. Neurotransmitters released presynaptically can bind to their postsynaptic receptors, the inhibitory γ-aminobutyric acid (GABA)ergic receptors or the excitatory glutamate receptors. Once released, glutamate activates a variety of postsynaptic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainate, and metabotropic receptors. The activation of the receptors triggers downstream signaling cascades generating a vast array of effects, which can be modulated by numerous auxiliary regulatory subunits. Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy. Therefore, it is important to identify the mechanisms involved in the regulation of synaptic transmission, which may serve as an essential component in the pathogenesis of epilepsy [Epilepsia.2012 December; 53Suppl9:41-58].

Regulators of postsynaptic neurotransmission ionotropic glutamate receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], N-methyl-D-aspartate [NMDA], play vital role in the regulation of synaptic transmission and thereby reduce the progression of epileptic seizures. The imbalance between AMPA receptors and calcium permeable AMPA receptors has been related to epileptogenesis [Tanaka et al., 2000].

Krestel et al. (2004) has showed that AMPA types of receptors enact a greater role in circuit hyperexcitability. The basic mechanism of neuronal excitability is the action potential, a hyperexcitable state can result from increased excitatory synaptic neurotransmission, decreased inhibitory neurotransmission, an alteration in voltage-gated ion channels, or an alteration of intra- or extra-cellular ion concentrations in favor of membrane depolarization.

Voltage-gated ions channels (VGICs), extensively distributed in the central nervous system (CNS), are responsible for the generation as well as modulation of neuroexcitability and considered as vital players in the pathogenesis of human epilepsy, by regulating the shape and duration of action potentials (APs). Particularly, genetic alterations or abnormal expression of voltage-gated sodium channels, voltage-gated potassium channels, and voltage-gated calcium channels are proved to be associated with epileptogenesis. The dysfunctional VGICs are like the blasting fuse for neuronal hyperexcitability and high-frequency neuron firing. Novel VGIC modulators are potentially an effective strategy for the development of novel antiepileptic drugs. Individualized precise treatment using matching VGIC drugs will provide novel research directions and antiepileptic strategies [Zhang, S., Zhu, Y, Cheng, J, & Tao, J. (2019).Ion Channels in Epilepsy].

As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting neuronal excitability, AMPA receptor antagonists markedly reduce or abolish epileptiform activity and confer seizure protection in a subject.

NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning, and memory. Often, the trigger for these dynamic movements is the activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval [Acta Neurologica Scandinavica127(s197) April 2013].

Also, it is observed that NMDA receptor antagonists sometimes induce “psychotomimetic” side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anaesthesia, and learning and memory deficits. Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs.

Further NMDA antagonists are supposed to cause neurotoxicity in humans in the form of Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAN). It is a form of potential brain damage due to drugs that have been studied experimentally and have produced neuronal damage.

In view of the physiological constraints associated with NMDA receptor inhibitors or antagonist, its use in the treatment of epilepsy is possibly less effective.

On the other hand, the inventors of present invention have found that active, non-competitive AMPA receptor antagonists are potential candidates for reducing progression of epilepsy.

Interestingly, the perampanel, a high-potency, orally active non-competitive AMPA receptor antagonist, supports the concept that AMPARs are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.

Further, EP Patent No. 1764361B1 discloses three anhydrous crystalline forms of perampanel and process for preparation thereof. However, perampanel has found to be less effective in certain types of seizures.

Therefore, the need arises to find out effective molecules that modulate AMPA receptors or inhibit AMPA receptor activity, that have potential to reduce excessive excitatory responses and may be promising future antiepileptic drugs (AEDs), with no adverse effects.

Although adverse effects can occur with all AEDs, among them CNS effects are the most prevalent ones. The failure of an AED regimen may be the result of unacceptable adverse effects (intolerance), inadequate seizure control (inefficacy) or a combination of both.

Further, literature has suggested that levetiracetam leads to behavioral side-effects such as aggression, hostility and nervousness in children with epilepsy compared to children who do not use levetiracetam.

Mood disorders, notably anxiety and depression, are common comorbidities in epilepsy that may be associated with AED therapy. Overall, adverse effects are a major reason for AED discontinuation. The future of epilepsy treatment awaits a “clean” AED that truly does not cause adverse effects in most patients. Further antiepileptic drugs are often insufficient to obtain seizure control and non-pharmacological interventions are often required. Currently available medications simply suppress seizure symptomatically, but do not appear to prevent seizure-induced brain injury or reverse the underlying mechanisms of epileptogenesis. Thus, it is now widely recognized that novel therapies for epilepsy need to be developed that have neuroprotective and antiepileptogenic properties.

In recent days, diet therapy is utilized in some patients with specific forms of epilepsy. Dietary therapies can provide control of seizures in patients with drug refractory epilepsy. There are several types of dietary therapies, all of which are high in fat, restrict carbohydrates to some extent, and are associated with ketosis. In the classical ketogenic diet introduced into clinical practice in the 1920s, the fat component is provided by long-chain triglycerides (LCTs). The medium-chain triglycerides (MCT) diet can be effective in seizure management and enhanced dietary intake of saturated fatty acid may provide additional therapeutic benefit.

The MCTs are mixed triglycerides of saturated fatty acids with a chain length of 6 to 12 carbon atoms, mainly C8 (caprylic acid) and C10 (capric acid). MCT oil can be obtained by direct or molecular distillation of virgin coconut oil. Particularly, MCT oils find many applications in cosmetics. It functions as a skin conditioning agent—occlusive as it slows the loss of water from the skin by forming a barrier on the skin's surface. It alters the thickness of liquid products and acts as a viscosity controlling agent.

The advance studies in recent days ensure that, treatment of adults with drug-resistant epilepsy, who show poor compliance to the stringent dietary regimen necessary for the MCT diet, may better tolerate a normal diet with just added fatty acid with C-10 carbon chain called decanoic acid, e.g., in the form of a triglyceride. Despite the long chain, the MCTs are more ketogenic than the LCTs.

The MCT ketogenic diet is widely considered to function by the generation of ketones, in the treatment of a range of disorders including epilepsy, cancer, Alzheimer's disease, and diabetes. However, the underlying mechanisms of the diet is still largely unknown.

The role of medium chain fats, provided in the diet, involving direct inhibition of a key neurotransmitter receptor (the AMPA receptor), and through regulating cellular energy through PPARγ activation and mitochondrial biosynthesis have provided alternative therapeutic approach that need to be explored. Understanding the role of AMPA, PPAR and mitochondrial biosynthesis, in relation to MCT ketogenic diet-responsive disorders may provide novel therapeutic targets and facilitate the development of new pharmacological and dietary treatments to achieve long-term remission from epileptic seizures.

Recently, it has been accomplished that decanoic acid has antiseizure effects at clinically relevant concentrations in vitro and in vivo [Neuropharmacology.2013 June; 69:105-14]. Further in vivo pharmacokinetic data indicates that decanoic acid penetrates the blood-brain barrier. The data suggests that decanoic acid directly contributes to the therapeutic effect of the MCT ketogenic diet. Indeed, decanoic acid is more potent than valproic acid (a branched chain fatty acid isomer of octanoic acid), that is commonly used in the treatment of epilepsy.

Decanoic acid has completely blocked epileptiform activity generated by decreasing GABAergic inhibition or potentiating NMDA receptor currents. This supports an antiseizure effect of the decanoic acid component of the MCT diet, rather than diet-derived ketones [Dis Model Mech.2012 January; 5(1):115-24].

Further, decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, to exhibit antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel [Brain.2016 February; 139(2): 431-443]. Decanoic acid, a component of medium chain triclycerides, contributes to seizure control through direct AMPA receptor inhibition.

Acute anticonvulsant or antiepileptic or antiseizure effects of decanoic acid (DA) also known as “capric acid”, C10 fatty acid is reported in the state of art.

EP Patent Application No. 3644985A1 discloses decanoic acid for use in treating epilepsy, wherein the decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

WO2018/189113A1 discloses a composition comprising a decanoic acid to octanoic acid ratio of 70:30 to 90:10 wt/wt for use in treating epilepsy or controlling epileptic seizures.

Further, it is reported that oral administration of C10 could increase anti-seizure activity in patients with MCT KD [Epileptic Disord2019; 21 (4): 366-9]. Sodium caprate, a medium chain fatty acid, increases the paracellular permeability through enlarging the tight junctions, thereby expanding paracellular routes for water-soluble, low lipophilic, and poorly absorbable drugs [AAPS PharmSciTech.2010 March; 11(1): 372-382].

Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle, whereby the promoter and payload must be co-released in high concentrations at the small intestinal epithelium to generate significant but rapidly reversible increases in permeability.

Conversely, decanoic acid and its metallic salt such as sodium caprate are having certain physiological limitations. C10 has the capacity to cause superficial damage to the intestinal epithelium in vivo. Further, C10 should be safe for use in high concentrations in oral dosage forms that may need to be given repeatedly even on a long-term basis. However, it might not be advisable to administer C10 formulations contemporaneously with other drugs that have the potential to elicit gastrointestinal side effects (e.g., NSAIDs, alcohol, etc.), nor to subjects with inflammatory bowel disease where basal intestinal permeability is already increased.

Further, it is observed that fatty acids like DA or its sodium salts are unsuitable for chronic administration due to its acidic nature, poor palatability, and gastrointestinal side effects. To avoid acid or sodium overload, especially for long-term treatment, there is a need to find out alternative smooth administration approach where DA can be easily carried out through GI tract.

The inventors of the present invention have come up with enriched source of DA, in other words the inventors have found that prodrugs or precursors or inactive form of DA called “tridecanoin” or “tricaprin” provides significant amount of DA after administration unlike free DA or salts thereof and without any acidic overload. Tridecanoin or tricaprin is nothing but triacylglycerol in which capric acid (n-decanoic acid) is linked to glycerol by a three-molecule ester bond. This kind of triglyceride of DA provides suitable formulations to avoid acid overload in patients.

Interestingly, the use of triglycerides of octanoate (trioctanoin) and decanoate (tridecanoin) in “a regular non-ketogenic diet” shows anticonvulsant effect. Particularly, tridecanoin is anticonvulsant, antioxidant, and improves mitochondrial function [J Cereb Blood Flow Metab.2017 June; 37(6): 2035-2048].

Currently, it is believed that sustained neuronal electrical activity and seizures can lead to neuronal injury and death resulting from underlying biochemical mechanisms such as the formation of excessive ROS. This leads to oxidative stress-induced abnormal structural alterations of cellular proteins, membrane lipids, DNA, and RNA. Oxidative stress is an underlying mechanism in the initiation and progression of epilepsy and contributes to neuronal degeneration in the epileptic focus.

The generation of ROS following seizures and their contributions to seizure development and seizure-induced neuronal loss are measured by the free radical levels. The epileptiform activity results in free radical production and could be considered as a factor that induces cell death.

It is observed that NRF2-antioxidant response element (ARE) signalling pathway could represent an important target in protecting the brain from the damage induced by epileptic seizures. The NRF2 pathway has been considered for the treatment of epilepsy due to the presence of oxidative stress from altered steady-state glutathione levels during epileptogenesis. Moreover, the ketogenic diet profoundly alters redox processes, in part by increasing cellular glutathione levels via NRF2 pathway activation. Therefore, a clear rationale exists for validating the NRF2 pathway as antiepileptic or antiepileptogenic therapies.

Wang et al. [Brain Res.2014; 1544:54-61] evaluates the NRF2-ARE signalling pathway activation for protecting brain from seizure-mediated damage and ameliorating cognitive impairment and oxidative stresses induced by epileptic seizures by employing NRF2 activator-sulforaphane (SF).

Various antioxidant agents could provide neuroprotective effects in a variety of neurological diseases through the activation of the NRF2-ARE pathway. EP Patent Application No. 3573968A1, provides tetrahydroisoquinoline derivatives as NRF2 activators. U.S. Pat. No. 9,737,525B2 discloses sulfanyl tiazole molecules as activators of the NRF2/KEAP1/ARE for treating a neurodegenerative disorder.

A hybrid of melatonin and sulforaphane combines the effects of melatonin with NRF2 induction properties, for achieving improved neuroprotective properties [Journal List Br J Pharmacol.2015 April; 172(7): 1807-1821]. Activation of NRF2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. [Toxicol Appl Pharmacol.2017 Jul. 1; 326:43-53].

In view of the above, it is evident that mere use of one therapeutic target could not be sufficient to give significant result in neurological diseases like epilepsy, wherein AMPAR antagonist is not enough to protect from oxidative stress damage, reversely NRF2 activators have limitations in order to regulate neuronal hyperexcitability and synchrony in seizure conditions.

Astonishingly, the inventors of the present invention have developed innovative therapeutic approach by introducing exogenous blend comprising specific combination of AMPAR antagonist and NRF2 activators that ameliorate natural defense mechanisms in synergistic manner for managing progression of epileptogenesis without any side effects.

OBJECTIVES OF THE PRESENT INVENTION

The primary objective of the present invention is to provide a promising therapeutic approach, for treating seizure related disorders.

Another objective of the invention is to provide a cost-effective, side-effect-free nutritional composition for treating neurological condition characterized by two or more unprovoked seizures or recurrent seizures.

Yet another object of the invention is to provide a nutrient based approach enriched with triglyceride and antioxidant for reducing the progression of epileptogenesis or fibrosis.

Further objective of the invention is to provide a combination of biologically active, safe, non-toxic, and naturally derived nutrients for treating epileptic seizures.

Another objective of the invention is to provide natural treatment in patients with epileptic seizures that leads to seizure-free status without adverse effects.

Yet another object of the invention is to provide natural remedy for treating chronic inflammatory diseases like fibrosis.

SUMMARY OF THE PRESENT INVENTION

To meet the above objectives, the inventors of the present invention carried out thorough experiments to establish significant effects of the bioactive ingredients or food ingredients or nutrients or exogenous naturally safe agents present in the composition that ameliorate abnormally excessive or synchronous neuronal activity in the brain.

In a particular aspect, the invention relates to synergistic nutritional compositions comprising therapeutically active nutrients along with pharmaceutically acceptable carriers for regulating unusual electrical activity in the brain.

In another particular aspect, the invention provides novel synergistic nutritional compositions comprising synergistic combination of non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists; and nuclear factor erythroid 2-related factor 2 (NRF2) activators, present in suitable weight ratio, along with pharmaceutically acceptable excipients, wherein AMPAR antagonists are precursors of decanoic acid or triglycerides of decanoic acid such as tridecanoin or tricaprin; and (NRF2) activators are selected from the group consisting of L-ergothioneine, isothiocyanate, melatonin either alone or combination thereof.

In another aspect, the present invention provides naturally occurring saturated fatty acid based synergistic nutritional compositions for regulating sudden, uncontrolled electrical disturbance in the brain (epileptic seizures).

In exemplary aspect, the present invention provides nutritional antiepileptic/antiseizure remedy comprising synergistic combination of tricaprin and ergothioneine, which are present in specific weight ratio, along with pharmaceutically acceptable carriers.

In the present invention, the AMPA receptor antagonist markedly reduces or abolishes epileptiform by reducing neuronal hyperexcitability and regularizing voltage-gated ion channels (VGICs). Further, AMPA receptor antagonist increases ATP turnover and proton leak in mitochondria, which reduces oxidative stress to protect the brain from seizures and damage.

Simultaneously, NRF2 activator inhibits seizure-induced neuronal cell death by regulating NRF2/KEAP1/ARE antioxidant signalling pathway that protects neurons against oxidative damage and excitotoxic damage. The NRF2-ARE signalling pathway activation blocks reactive oxygen species or ROS production, mitochondrial depolarization, and cell death in a subject with a sudden surge of electrical activity in the brain.

In another aspect, the invention provides a cost effective, non-toxic, efficient and environmentally safe, exogenous nutritional composition comprising synergistic combination of food grade ingredients for reducing neuronal hyperexcitation and neuronal loss associated with seizures without adverse effects that are generally related to first- and second-generation AEDs.

In further aspect, the present invention provides novel and potent synergistic nutritional composition for treating fibrotic conditions.

In yet another aspect, the invention relates to synergistic nutritional compositions comprising combination of AMPAR antagonist which is present in a range of 1 to 5000 mg; and NRF2 activator which is present in a range of 1 to 1000 mg along with pharmaceutically acceptable excipients/carriers, optionally in presence of bioenhancer.

In yet one more aspect, the invention provides synergistic medicinal composition which is useful for treating seizure disorders such as epilepsy, reflex epilepsy, epileptic seizures, nonepileptic seizures, provoked seizures, idiopathic generalized epilepsy, convulsion, absence seizures, atonic seizures, tonic seizures, clonic seizures, myoclonic seizures, febrile seizure, focal seizures, temporal lobe seizures, occipital lobe seizures, parietal lobe seizures, nocturnal epilepsy, fibrotic diseases and mitochondrial dysfunction in diabetes.

ABBREVIATIONS

DA: Decanoic acid/Capric acid/C10MCT: Medium-chain triglycerideNRF2: Nuclear factor erythroid 2-related factor 2NFE2L2: Nuclear factor erythroid-derived 2-like 2KEAP1: Kelch-like ECH-associated protein 1ARE: Antioxidant response elementAMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidAMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptorsNMDA: N-methyl-D-aspartic acidGABA: Gamma-aminobutyric acidPPAR-γ/PPARG: Peroxisome proliferator-activated receptor gammaEGT: L-ergothioneineSFN: SulforaphaneKD: Ketonic DietGPR84: G-protein coupled receptor 84/proinflammatory receptorGPR40: G-protein coupled receptor 40/Free fatty acid receptor 1 (FFA1)

