NMDA Receptor Pathways as Drug Targets in CNS Therapeutics

NMDA Receptor Pathways as Drug Targets in CNS Therapeutics 1. Introduction: Glutamate is the king of excitatory neurotransmission in the central nervous system (SNC) and acts on receptors located at the presynaptic terminal and in the postsynaptic membrane at synapses in the brain and spinal cord (Ghasemi and Schachter, 2011). Although glutamate was known to have central nervous system effects for more than 75 years, it was not until 1984 that it was truly acknowledged as fulfilling the criteria of a neurotransmitter. (Niciu et al., 2012). Glutamate receptors are divided into two broad categorizations: ionotropic and metabotropic receptors. Ionotropic glutamate receptors are ion channels that flux cations (Ca2+, Na+) and open the channels in response to agonist binding. On the other hand, metabotropic receptors activate or inhibit second messenger systems via interactions with cognate G-proteins. (Niciu et al., 2012). Ionotropic glutamate receptors can be subdivided into three large families: AMPA receptors (AMPARs), kainate receptors and NMDA receptors (NMD ARs). Since three decades ago, the discovery NMDARs have kept fascinating neuroscientists while their dysfunctions are also involved in various neurological and psychiatric disorders, including stroke, pathological pain, neurodegenerative diseases and schizophrenia. (Paoletti et al., 2013) Fortunately, the NMDA receptor complex is composed with modulatory sites, and the late 1970s and 1980s saw the development of agonists, antagonists and modulators acting at different binding sites. In the last decade, the molecular biology of the NMDA receptors has been defined, and now it is known that these receptors are formed of an NR1 subunit in combination with one or more NR2 or less commonly an NR3 subunit. (Kemp and McKernan, 2002). 2. Molecular mechanisms NMDA receptors are named after their selective agonist N-methyl-D-aspartate. The receptors are multisubunit complexes associating NR1, NR2 and, more rarely, NR3 subunits. NR2 and NR3 subunits exist as four and two subtypes, respectively (NR2A-D and NR3A-B). NR1 exists as seven subtypes (NR1a–g) (Mony et al., 2009) The receptors are heterotetramers comprising a combination of NR1, NR2A-D and  NR3A-B subunits. The main agonists are glutamate and NMDA, with their binding site on NR2 subunits, while the binding site for the co-agonists D-serine and glycine is located on NR1 and NR3 subunits and the T most common composition of NMDA receptors includes two NR1 and two NR2 subunits, or two NR1, one NR2 and one NR3 subunits (Dzamba et al., 2013). A common structure for glutamate receptors contains an extracellular amino-terminal domain (ATD) for various modulatory functions, extracellular S1S2 domains for agonist binding, an ion channel domain with four transmembrane segments (M1â⠂¬â€œ4) for gating and ion permeation, and a carboxy-terminal domain for communicating with intracellular milieu Fig 1 (Majdi and Chen, 2009). Pharmacological regulation of the NMDAR depends on effects on unique combinations of subunit-specific binding sites. Once glycine coagonist attaches to its site, the glutamate can activate the ion channel and the Na+ and Ca2+ rush in. The Mg2+ blocks channel pore and the blockade is relieved by cellular depolarization, which has implications for synaptic plasticity, especially long-term potentiation (LTP). (Ghasemi and Schachter, 2011) Most compounds that act at NMDA receptors interact with one of 4 drug binding sites on the NMDA receptor complex, the glutamate or glycine binding sites, the ion channel pore, or a binding site on the regulatory NTD. The first compounds identified were agonists and antagonists of the glutamate like D-ÃŽ ±-aminoadipic acid and D-2-amino-5phosphonopentanoic  acid (D-AP5) then glycine competitive antagonists like 7-chloro-5-iodokynurenic acid and partial agonists were identified. It was also soon recognized that some dissociative anesthetics (e.g. ketam ine and phencyclidine) were NMDA receptor blockers and the widely used inhibitor MK-801 was shown to be a potent NMDA receptor channel blocker Fig 2 (Monaghan et al., 2012). Another important aspect of NMDA receptor pharmacology is modulation by posttranslational modifications, such as phosphorylation of the intracellular C-terminal of NR2 subunits. NMDA receptor-mediated calcium increases activate many downstream targets like protein kinase C (PKC) and the Modulation by protein kinase C (PKC) depends on NMDA receptor subunit composition; NR2A- and NR2B-containing receptors are potentiated by PKC activation, whereas NR2Cand NR2D containing receptors are unaffected or inhibited by PKC. PKC phosphorylates the NR1 subunit at serine 890 (S890) in the C1 cassette. The potentiatory effects of PKC are not dependent on phosphorylation of NR1, but inhibitory effects are blocked by mutation of S890 or removal of the C1 domain. The NMDA receptor function is also modulated by MAGUK protein fami ly which controls the NMDA receptor localization, the binding to the scaffolding proteins plays a major role in the control of downstream signals resulting from receptor activation. It thought that synaptic NMDA receptors are retained at the synapse by an attachment to PSD-95 through a PDZ interaction with the NR2 subunits.(Gardoni and Di Luca, 2006) 3. Therapeutics A high number of central nervous system disease states in which neuronal cell death is associated to glutamate induced excitotoxicity could be treated by blocking NMDA receptors such as neurological disorders including ischemia, epilepsy, brain trauma, dementia, and neurodegenerative disorders. à ¯Ã¢â‚¬Å¡Ã‚ · Ischemia : it has been shown that loss of calcium homeostasis may be an important mechanism of ischemic brain damage. Ischemia also resulted in a decrease in the size of protein complexes containing PSD-95. In addition, transient cerebral ischemia increases tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B. Recent studies suggested to treat stroke transducing neurons with peptides able to disrupt the interaction of NMDA receptor NR2B subunits with the postsynaptic density protein PSD-95. This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx and protected cultured neurons from excitotoxi city. .( Gardoni and Di Luca, 2006). Many NR1/NR2B antagonists, including ifenprodil, eliprodil and the selective and potent congeners, Ro 25,6981 and CP-101,606, offer promise in preclinical models of ischaemia (Chazot, 2004) à ¯Ã¢â‚¬Å¡Ã‚ · Epilepsy: Recent work has suggested that hyper-phosphorylation of NR2B may results in hypersensitivity to the endogenous transmitter, and induction of neuronal hyperexcitability and epilepsy. Furthermore, kainic acid-induced alters tyrosine phosphorylation of NR2A and NR2B receptors. Interestingly, the high affinity NR2B compound, Ro 63-1908 was shown to be active versus acoustic-induced convulsions and NMDA-induced seizures at 4.5 mg/kg ip and 2.31 mg/kg iv, respectively and no adverse cardiovascular, motor deficits or other CNS sideeffects were observed at these active. (Chazot, 2004). à ¯Ã¢â‚¬Å¡Ã‚ · Huntingtons disease: The normal huntingtin binds to PSD-95 scaffold protein which inhibit the NMDA receptor Overexpression of the normal huntin gtin N terminus significantly attenuates neuronal toxicity induced by both NMDA receptors and the mutated huntingtin. This suggests that PSD-95 is a mediator of neuronal toxicity induced by NMDA receptors and mutated huntingtin. In addition, in a transgenic model of Huntington disease. Other studies show that expression of mutant htt (but not wild-type htt) in combination with NR1/NR2B increases cell death compared to  transfection of only NMDA receptor subunits, suggesting a role for NR1/NR2B NMDA receptors in cell death mediated by mutant htt .As NR2B antagonists block most of the NMDA receptor mediated currents in neuronal models of Huntington, the selective localization of NR2B in the striatum may also play a role in the efficacy of NR2B antagonists against cell death in models of Huntington.( Gardoni and Di Luca, 2006). à ¯Ã¢â‚¬Å¡Ã‚ · Alzheimers disease : In animal models, NR2B subunit expression decreases with age, which correlates well withreduced Long Term Potentiation (L TP) and inferior cognitive performance. The NR1/NR2B subtype decreases, in comparison to other subtypes, in the frontal cortex of aged humans while overexpression of the forebrain NR2B subunit in transgenic mice has been shown to have profound beneficial effects upon cognitive performance. Such information suggests that controlled potentiation of the NR2B may offer a novel strategy for treating cognitive disabilities. (Chazot, 2004). à ¯Ã¢â‚¬Å¡Ã‚ · Parkinsons disease: At the molecular level, alterations of NMDA receptor subunits localization in striatum have been described in Dopamine-denervated rats as well as in L-DOPA-treated dyskinetic monkeys. In particular, NR2B subcellular redistribution from synaptic to extrasynaptic sites represents the key element in the complex modifications of the glutamatergic synapse in L-DOPA-induced dyskinesia. On the other hand, recent studies in primates suggested that upregulation of NR2A abundance in synaptosomal membranesmay be an important pla yer in L-DOPA induced dyskinesias. And recently, two studies described results on the effects of NR2B selective NMDA receptor antagonist CP-101,606 on L-DOPA induced dyskinesia in two different models of experimental parkinsonism.( Gardoni and Di Luca, 2006). à ¯Ã¢â‚¬Å¡Ã‚ · Psychosis : Studies have suggested that the NR2B has role in psychotic disorders, including schizophrenia and bipolar disorder. The mRNA encoding the NR2B subunit and NR1/NR2B-type binding sites have been shown to be selectively increased in hippocampal and cortical regions, Recent work has identified a novel T200G variant located in the NR2B promoter, which endows dysfunction of the NR2B subunit. The frequency of this variant was significantly up-regulated in a schizophrenia group compared to a control group. The possible link between these observations is yet to be investigated. (Chazot, 2004). à ¯Ã¢â‚¬Å¡Ã‚ · Pain: Studies suggest that the NR2B subunit plays distinct roles in acute and chronic pain states, re cently NR2B antagonists were developped, including Ro 25,6981, CP -101,606, PD 174494 and PD 196860, are effective in a range of animal chronic pain models with a wide separation between anti-hyperalgesic and side-effect doses . . (Chazot, 2004). 4. References Chazot, P. L. (2004). The NMDA receptor NR2B subunit: A valid therapeutic target for  multiple CNS pathologies. Curr. Med. Chem. 11, 389-396. Dzamba, D., Honsa, P. and Anderova, M. (2013). NMDA receptors in glial cells: Pending  questions. Current Neuropharmacology 11, 250-262. Gardoni, F. and Di Luca, M. (2006). New targets for pharmacological intervention in the  glutamatergic synapse. Eur. J. Pharmacol. 545, 2-10. Ghasemi, M. and Schachter, S. C. (2011). The NMDA receptor complex as a therapeutic  target in epilepsy: A review. Epilepsy Behavior 22, 617-640. Kemp, J. A. and McKernan, R. M. (2002). NMDA receptor pathways as drug targets. Nat.  Neurosci. 5, 1039-1042. Majdi, M. and Chen, H. V. (2009). NMDA-gated ion channel research and its therapeutic  potentials in neurodegenerative diseases: A review. Journal of Receptor, Ligand and Channel Research 2, 59-73. Monaghan, D. T., Irvine, M. W., Costa, B. M., Fang, G. and Jane, D. E. (2012).  Pharmacological modulation of NMDA receptor activity and the advent of negative and  positive allosteric modulators. Neurochem. Int. 61, 581-592. Mony, L., Kew, J. N., Gunthorpe, M. J. and Paoletti, P. (2009). Allosteric modulators of  NR2Bà ¢Ã¢â€š ¬Ã‚ containing NMDA receptors: Molecular mechanisms and therapeutic potential. Br. J.  Pharmacol. 157, 1301-1317 Niciu, M. J., Kelmendi, B. and Sanacora, G. (2012). Overview of glutamatergic  neurotransmission in the nervous system. Pharmacology Biochemistry and Behavior 100,  656-664. Paoletti, P., Bellone, C. and Zhou, Q. (2013). NMDA receptor subunit diversity: Impact on  receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience 14, 383-400.

Economics at the University of Pennsylvania Essay

Although I want to major in Economics at the University of Pennsylvania, I have a passion for poetry and prose, and I would love more than anything to develop my writing skills in Penn’s School of Arts and Sciences. That program provides the disciplined and distinguished qualities that I seek. One must be a great reader before becoming a great writer, so I indulge in books of every genre to expand my range of knowledge. Literature brings me great joy, and I will strive to integrate my fondness for reading and writing into my college experience. Penn’s English Department is unique in that it provides the opportunity for students to place an emphasis on studies in creative writing. Within that framework, I want to channel my passion for poetry into academia. As founder and president of Shandong Normal University Literature Association, if accepted, I plan to visit the Kelly Writers House religiously as a way to satisfy my perpetual craving for remarkable literature. I envision myself grabbing a turkey and cheese sandwich with no mayonnaise at the 1920 Commons, then rushing off to the Kelly Writers House with an armful of books by Maya Angelou and Eric Schlosser. Gathered in a tight circle of chairs, I want to share professional works with fellow literature lovers. We will offer our own daring lines of free verse, swap suggestions, compliments, and light-hearted laughs. During workshops, my very soul seeps steadily through an invisible tube from brain to ballpoint. This complex phenomenon of input-output produces painstakingly arranged ink on paper, a painting made of letters. On my way to a morning class on modern American poetry, I will pass Oldenberg’s famed Split Button and acknowledge Mr. Franklin sitting upright in his chair. After the lecture, I can envision Professor Josephine Park and I conducting research by analyzing the influence of conflicts between America and East Asia on Asian-American texts. As part of the Penn family, I will converse with colleagues, sisters, and brothers that destiny forgot to recognize. Then, I will tutor secondary school students about reading and writing through the outreach program. Having been featured in a myriad of written works and publishing my own collections, I will roll up my sleeves and organize literary pieces in the weekly undergraduate magazine, First Call. As evening emerges, I will bike to the Van Pelt Library, work comfortably in my favorite armchair, and complete the finishing touches on a Second World War paper. Traveling to other parts of the City of Brotherly Love, study group friends and I will order a few Philly Cheesesteaks from Pat’s King of Steaks for dinner. My roommate, with lips coated in frothy toothpaste, will open the door when I get back. After taking a shower, I will dry my hair on a blue polka dot towel, sit on my bed, and chortle cheerfully while my roommate chatters about the highlights of her day. Then I will read an article about the Penn Museum from The Daily Pennsylvanian. After turning off the lights and setting my alarm clock for 6:00am, I will drape my jogging shorts and shirt on a chair for the morning. Before drifting off to sleep, I will fondly recall submitting my application to Penn, and smile in the quiet of my room, happy to be here at last.

The Picture Of Dorian Gray - 1680 Words

At the height of his success, Oscar Wilde wrote his novel The Picture of Dorian Gray, which follows the life of a young man living in late nineteenth-century London. The novel shares a similar storyline with that of Wilde’s life, as Wilde wrote it in attempt to justify his homosexuality. The protagonist of the novel, Dorian Gray, enters the story an innocent man, but eventually becomes corrupt due to his need for instant pleasure. Wilde recognizes that the topic of his homosexuality brings up the importance of challenging society, but he uses Dorian’s character to depict the dangers of completely disobeying society. He does so by making Dorian succumb to the temptations of hedonism, the pursuit of instant pleasure through any means possible, in this novel. Wilde faced persecution by society, and hoped that through his novel he could show society the truly corrupt actions of people, therefore proving that his homosexuality does not compare to morally wrong actions like m urder. Wilde wanted society to understand that life’s meaning involves living with some rejection to societal acceptance and morals, and that people should find a stable balance between the rights and wrongs of society and live upon that as he did. After having married and raising two children, Oscar Wilde discovered his homosexuality upon meeting John Gray in 1889. Perhaps because John felt indifferent towards Wilde, Wilde launched a campaign to win John’s affection. The resulting relationship became theShow MoreRelatedThe Picture Of Dorian Gray1482 Words   |  6 Pagesreturn give to the same story† (Foster 185-186). One book that is a part of Foster’s story is Oscar Wilde’s The Picture of Dorian Gray. In this essay, Thomas Foster’s methods regarding both symbolism and  ¬Ã‚ ¬Ã‚ ¬Ã‚ ¬heart disease from his book, How to Read Literature Like a Professor will be discussed and applied to one of Oscar Wilde’s novels. Throughout his nove l, The Picture of Dorian Gray, Oscar Wilde uses the portrait of the young protagonist as a symbol of many things, one of them being a mirror. WildeRead MoreThe Picture Of Dorian Gray Essay1460 Words   |  6 PagesAs seems to be the theme of Oscar Wilde’s book, The picture of Dorian Gray, art an beauty are both the same, yet they are different. But how can this be? Well, beauty and art are intertwined the moment art is used to capture a sliver of pure beauty, in order to make that moment last forever. According to Lord Henry, â€Å" Yes, Mr. Gray, the gods have been good to you. But what the goods give can easily be taken away. You only have a few years in which to live really, perfectly, and fully† (Wilde Pg.Read MoreThe Picture Of Dorian Gray1432 Words   |  6 PagesIn The Picture of Dorian Gray by Oscar Wilde, we see how the different characters show their love of beauty and pleasure and the affects they have on the main character: Dorian Gray. Each of the three main characters, Basil Hallward, Lord Henry Wotton, and Dorian Gray portray a part of how the author felt about himself and the world around him. â€Å"Basil Hallward is what I think I am: Lord Henry what the world thinks of me: Dorian what I would like to be- in other ages, perhaps† (qtd. in Bloom pg. 117)Read MoreThe Picture Of Dorian Gray1576 Words   |  7 PagesTransformation in Literature Greek Philosopher Heraclitus once said â€Å"There is nothing permanent except change†. In Oscar Wilde’s The Picture of Dorian Gray, the theme of transformation is constant throughout the novel; however it is not portrayed as something that is permanent. Through the protagonist’s transformation, Oscar Wilde s novel is suggesting that the hedonistic lifestyle, a lifestyle where gaining pleasure is the main goal of a person’s life, may seem like it is an exciting and wonderfulRead MoreThe Picture Of Dorian Gray965 Words   |  4 Pages When looking at Frankenstein and The Picture of Dorian Gray, it is clear that Frankenstein is a novel that can be placed into both the gothic and horror genre, although it is a gothic novel secondary to it being a horror novel; The picture of Dorian Gray isn’t so clear in this regard. On a first reading, one may assume the story to be gothic literature and only gothic literature because of the sheer amount of gothic characteristics and elements that the text presents that include, but are not limitedRead MoreThe Picture Of Dorian Gray957 Words   |  4 PagesWilde explores the theme of outsiders in his 1890 novel, The Picture of Dorian Gray. He infuses what it means to be an outsider in almost every character in the story. The most important of these characters are Dorian Gray, Henry, and Basil. Each show what it means to be an outsider in his own individual way; whether it is an outsider among society, among a group of friends, or from a person’s own self. The main character, Dorian Gray, possesses most attributes of being an outsider. The most obviousRead MoreThe Picture Of Dorian Gray971 Words   |  4 PagesIn Oscar Wilde’s Popular nineteenth century novel, the Picture of Dorian Gray demonstrates the importance of the aesthetic movement in Victorian England. This suggests youth and physical attractiveness is emphasized and are valuable additions to society. Therefore, what matters to Dorian, is not the internal goodness an individual possesses but the appearance they present. Consequently, Dorian is able to forget the violent acts he commits as long as he appears beautiful on the outside. Since externalRead MoreThe Picture Of Dorian Gray1211 Words   |  5 PagesIn The Picture of Dorian Gray, Oscar Wilde warns against immorality, vanity and selfishness using his protagonist’s downfall to show the dangers of overindulgence and depravity. The preface is contradictory and reveals that Wilde’s beliefs on art and its ties to morality were inconsistent. He appears to be trying to show that we shouldn’t subscribe to just one clear ideal without questioning it or considering other opinions. However, it’s clear throughout the book that there is a strong moral ideologyRead MoreThe Picture Of Dorian Gray1283 Words   |  6 PagesWhat does the fall of man, Oscar Wilde novel The Picture Of Dorian Gray, and Shakespeare’s Macbeth all have in common? They all have the same theme of the fall of man and break in the perfect union they once where in. The novels all start with man in perfect union, then sin enters and chaos starts and it eventually leading to their death or downfall. The Fall of man, Shakespeare’s Macbeth and Wilde’s novel The Picture Of Dorian Gray tightly follow the archetype of the fall of man this is all illustratedRead MoreThe Picture Of Dorian Gray864 Words   |  4 PagesWhile God in America: A New Adam illustrates the positive effects influence has on an individual, The Picture of Dorian Gray by Oscar Wilde exhibits the negative consequences influence has on an individual who conforms to society’s beliefs. Compared to the Spanish, the Puritans succeeded in the teachings of their religion because they endorsed individual thought rather than collective thoughts. Upon their arrival to New Mexico, the Spaniard missionaries believed it was their mission from God to â€Å"save

Approaching Questions beyond Science Philosophy vs Religion - Free Essay Example

Sample details Pages: 4 Words: 1236 Downloads: 8 Date added: 2019/03/11 Category Religion Essay Level High school Tags: Science vs Religion Essay Did you like this example? Dread—the driving force of some of the greatest minds to find answers to life’s biggest questions. An equally perplexing challenge is how to begin tackling such problems. By focusing on one dilemma and comparing how both schools of thought attempt to solve the problem, a hint may be revealed as to which approach to prefer. Philosophy is based on open discussion and human reasoning, as a result it is better suited than religion to explore what is beyond science—the meaning of life. Within themselves, philosophy and religion do not produce a satisfactory answer because of disagreement. Two well known philosophers such as Friedrich Nietzsche and Aristotle give starkly contrasting answers to life. Nietzsche argues in his book â€Å"The Birth of Tragedy† that there is no inherent meaning in life at all, instead it is art that gives it meaning (p. 52). While, Aristotle would say that happiness is a central purpose of human life (pp. 2). Religion disagrees within itself just as much evidently. Each spirituality has its own entirely different doctrine. Disagreement is at the core of this search for â€Å"The Answer†. Through open discussion, this becomes a weakness for religion but a strength for philosophy. Don’t waste time! Our writers will create an original "Approaching Questions beyond Science Philosophy vs Religion" essay for you Create order The principle of symposium within religion was terminated when each religious historical figure claims his doctrine as the ultimate truth. Jesus Christ establishes Heaven and Hell as the afterlife in Christianity. Siddhartha Gautama, founder of Buddhism, proposes a path to enlightenment to go beyond life and pain. This list of differing teachings can go on indefinitely. The crux of disagreeing beliefs among religions is that it is treated as a dividing force. Any disagreement is enough grounds to simply separate oneself from a denomination and start their own. Albeit the controversy was not on the meaning of life, the most famous example of this was when Martin Luther started a cascade of dividing denominations with his 95 theses. Disagreement was present in the Catholic Church, their solution—division. Although relatively harmless when compared to religious crusades, the division of religion has only made the search for a single agreeable teaching even murkier because the amo unt of doctrines claiming to be the ultimate truth multiplies. In religion, disagreement is a drawback because not only does it cause separation, it is counterproductive against humanity’s attempt at finding a solution. On the contrary, in philosophy, disagreement and discussion is at the heart of finding certain truths. Theorist Edmund Burke, in his dissertation â€Å"Of the Standard of Taste†, he demonstrates how two wine critics with differing critiques were partially wrong alone, but correct together. At a wine test, one critic tasted leather and another tasted iron while unknown to them there was a key on a leather strap at the bottom of the barrel. Both initially disagreed, but through open discussion, synthesized their findings and resulted in a true critique. This concept is not only limited to artistic taste, it is prevalent in all of philosophy. In other words, approaching â€Å"The Big Question† with open discussion and proactive synthesis aims humanity’s attempts in the correct direction. Moving on from how both schools of thought handle disagreement and approach an answer, one must step back and consider what their views are based on after all. In the school of philosophy, theories are based on human reason, rationality and logic. Although not all religious beliefs are this way, most divine beliefs are based on pure faith. If enough steps are retraced, then it becomes evident that an assumption is at the root of any theory deduced thereof. It does not necessarily immediately discount its validity or mean that they are not true. Such theories are to be taken with a grain of salt because of its inherent uncertainty. The advantage in philosophy is that it isn’t held back by uncertainty. Although religious beliefs on how to live life are hardly disputed, its claims on a higher power are based on an unverifiable argument and are indeed heavily disputed among religion. In Christianity, an elaborate and elegant afterlife is depicted, and Jesus is the guide to said afterlife. These claims are true, if Jesus without a doubt is indeed The Son of a Higher Power. The inability to neither prove or disprove Jesus’s divine affiliation, makes it a postulate at best—an assumption. This axiom ,based on pure faith, gives birth to Christianity and makes all theories of the divine derived from Jesus true. Islam’s axiom is Muhammad’s legitimacy as Allah’s prophet. Making a decision, or believing something to be true because of faith is, effectively a low risk gamble. Religion approaches the meaning of life by effectively gambling on an axiom, complicating the validity of i ts claims and falling on the wrong side of Occam’s razor, an english philosopher’s greatest contribution to human reasoning . In philosophy, it is Occam’s Razor that declutters the sea of countless theories on the meaning of life. His razor is a principle that states the explanation that makes the least assumptions should be prefered. Occam’s razor does not confirm the validity of a theory, instead it merely serves a guide as to which theory to employ. What heavily differentiates philosophy from religion is that, assumptions are hardly used, if not entirely avoided. The basis for a theory on philosophy is usually deduced logically from given information rather than postulated. After observing the similarities between the real world and art, Plato deduced that Art imitates life. In a modern world context, neuroscientist/philosopher Guillaume Thierry conducted an 18 year study on the brain and concluded that the meaning of life lies in our brains ability to deduce meaning at all (pp. 2). The key point from this is that philosophers observed the subject matter first then through human reasoning a nd logic, deduced a verifiable argument backed by empirical evidence. In other words, assumptions were avoided. Occam’s razor states that the simplest theories with the least assumptions should be sought first. Philosophy approaches the meaning of life through basing its theories on verifiable arguments, empowering its certainty and earning priority consideration in the search for an â€Å"answer†. Alas, philosophy is not perfect. Human reason is the pillar of philosophical thought, but it may just also be its crux. Since human reason is secular, it may only exist and operate within the secular realm—it is incapable of coming to a supernatural conclusion without making the leap of faith. Religion’s only advantage over philosophy is its ability to consider and theorize the celestial. Because the spiritual can neither be confirmed nor denied, this advantage is neutralized. In other words, philosophy’s limit is the heavenly realm, but because the divine realm cannot be confirmed the religious realm is no greater but no less than the known secular realm. Figuring out how to answer the meaning of life is just as daunting as the question itself. Religion approaches it by basing its theories on axioms. On the other hand, philosophy deduces principles through observation and reasoning. It also improves its current theories through finding common grounds among disagreement as an indication of a certain truth. Religion’s ability to consider the divine proves itself to be no less but no greater than secular reasoning. Considering Occam’s razor, overall certainty, and its principle of open discussion, philosophy is indeed the school of thought better suited to explore what is beyond our observable life.