'''Neuroprotection''' refers to the relative preservation of [[neuron]]al structure and/or function.<ref name="Casson_2012">{{cite journal |vauthors=Casson RJ, Chidlow G, Ebneter A, Wood JP, Crowston J, Goldberg I | title = Translational neuroprotection research in glaucoma: a review of definitions and principles | journal = Clin. Experiment. Ophthalmol. | volume = 40 | issue = 4 | pages = 350–7 | year = 2012 | pmid = 22697056 | doi = 10.1111/j.1442-9071.2011.02563.x }}</ref> In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation.<ref name="Casson_2012"/> It is a widely explored treatment option for many [[central nervous system]] (CNS) disorders including [[neurodegenerative diseases]], [[stroke]], [[traumatic brain injury]], [[spinal cord injury]], and acute management of neurotoxin consumption (i.e. [[methamphetamine]] overdoses). Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of [[neurons]].<ref name="overview of PD">{{cite journal |vauthors=Seidl SE, Potashkin JA | title = The promise of neuroprotective agents in Parkinson's disease | journal = Front Neurol | volume = 2 | issue = | pages = 68 | year = 2011 | pmid = 22125548 | pmc = 3221408 | doi = 10.3389/fneur.2011.00068 }}</ref> Despite differences in symptoms or injuries associated with [[CNS disorders]], many of the mechanisms behind [[neurodegeneration]] are the same. Common mechanisms include increased levels in [[oxidative stress]], mitochondrial dysfunction, [[excitotoxicity]], inflammatory changes, iron accumulation, and protein aggregation.<ref name="overview of PD"/><ref name="prospects">{{cite journal |vauthors=Dunnett SB, Björklund A | title = Prospects for new restorative and neuroprotective treatments in Parkinson's disease | journal = Nature | volume = 399 | issue = 6738 Suppl | pages = A32–9 |date=June 1999 | pmid = 10392578 | doi =10.1038/399a032 }}</ref><ref name="oxidative stress">{{cite journal | author = Andersen JK | title = Oxidative stress in neurodegeneration: cause or consequence? | journal = Nat. Med. | volume = 10 Suppl | issue = 7| pages = S18–25 |date=July 2004 | pmid = 15298006 | doi = 10.1038/nrn1434 }}</ref> Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own.<ref name="inflammation">{{cite journal |vauthors=Zádori D, Klivényi P, Szalárdy L, Fülöp F, Toldi J, Vécsei L | title = Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders | journal = J Neurol Sci | volume = 322| issue = 1–2| pages = 187–91|date=June 2012 | pmid = 22749004 | doi = 10.1016/j.jns.2012.06.004 }}</ref> Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are [[glutamate]] antagonists and [[antioxidant]]s, which aim to limit excitotoxicity and oxidative stress respectively.
== Neuroprotection ==
== Excitotoxicity ==
[[File:Neuronehisto.jpg|thumb|right|Histological image of neurons]]
{{main|Excitotoxicity}}
Glutamate excitotoxicity is one of the most important mechanisms known to trigger cell death in [[CNS disorders]]. Over-excitation of [[glutamate receptors]], specifically [[NMDA receptor]]s, allows for an increase in [[calcium]] ion (Ca<sup>2+</sup>) influx due to the lack of specificity in the ion channel opened upon glutamate binding.<ref name="inflammation"/><ref name="excitotoxicity">{{cite journal |vauthors=Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, Ma L, Cao R, Rao Z, Zhao G | title = Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting ca(2+) influx | journal = Cell. Mol. Neurobiol. | volume = 32 | issue = 1 | pages = 121–8 |date=January 2012 | pmid = 21811848 | doi = 10.1007/s10571-011-9742-x }}</ref> As Ca<sup>2+</sup> accumulates in the neuron, the buffering levels of mitochondrial Ca<sup>2+</sup> sequestration are exceeded, which has major consequences for the neuron.<ref name="inflammation"/> Because Ca<sup>2+</sup> is a secondary messenger and regulates a large number of downstream processes, accumulation of Ca<sup>2+</sup> causes improper regulation of these processes, eventually leading to cell death.<ref name="calcium">{{cite journal |vauthors=Sattler R, Tymianski M | title = Molecular mechanisms of calcium-dependent excitotoxicity | journal = J. Mol. Med. | volume = 78 | issue = 1 | pages = 3–13 | year = 2000 | pmid = 10759025 | doi =10.1007/s001090000077 }}</ref><ref name="glutamate receptor">{{cite journal |vauthors=Sattler R, Tymianski M | title = Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death | journal = Mol. Neurobiol. | volume = 24 | issue = 1–3 | pages = 107–29 | year = 2001 | pmid = 11831548 | doi = 10.1385/MN:24:1-3:107 }}</ref><ref name="progesterone">{{cite journal |vauthors=Luoma JI, Stern CM, Mermelstein PG | title = Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection | journal = J. Steroid Biochem. Mol. Biol. | volume = 131 | issue = 1–2 | pages = 30–6 |date=August 2012 | pmid = 22101209 | doi = 10.1016/j.jsbmb.2011.11.002 | pmc = 3303940 }}</ref> Ca<sup>2+</sup> is also thought to trigger neuroinflammation, a key component in all CNS disorders<ref name="inflammation"/>
=== Glutamate antagonists ===
'''Neuroprotection''' refers to the mechanisms and strategies used to protect the [[nervous system]] from injury and degeneration. The primary goal of neuroprotection is to prevent or slow the progression of [[neurodegenerative diseases]] and to limit the extent of damage following [[neurological injury]].
Glutamate antagonists are the primary treatment used to prevent or help control excitotoxicity in CNS disorders. The goal of these antagonists is to inhibit the binding of glutamate to [[NMDA receptor]]s such that accumulation of Ca<sup>2+</sup> and therefore excitotoxicity can be avoided. Use of glutamate antagonists presents a huge obstacle in that the treatment must overcome selectivity such that binding is only inhibited when excitotoxicity is present. A number of glutamate antagonists have been explored as options in CNS disorders, but many are found to lack efficacy or have intolerable side effects. Glutamate antagonists are a hot topic of research. Below are some of the treatments that have promising results for the future:
*Estrogen: [[Estradiol|17β-Estradiol]] helps regulate excitotoxicity by inhibiting NMDA receptors as well as other glutamate receptors.<ref name="LiuZhang2012">{{cite journal | vauthors = Liu SB, Zhang N, Guo YY, Zhao R, Shi TY, Feng SF, Wang SQ, Yang Q, Li XQ, Wu YM, Ma L, Hou Y, Xiong LZ, Zhang W, Zhao MG | title = G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors | journal = The Journal of Neuroscience | volume = 32 | issue = 14 | pages = 4887–900 | date = April 2012 | pmid = 22492045 | doi = 10.1523/JNEUROSCI.5828-11.2012 }}</ref>
*[[Ginsenoside]] Rd: Results from the study show ginsenoside rd attenuates glutamate excitotoxicity. Importantly, clinical trials for the drug in patients with ischemic stroke show it to be effective as well as noninvasive<ref name="excitotoxicity"/>
*[[Progesterone]]: Administration of progesterone is well known to aid in the prevention of secondary injuries in patients with traumatic brain injury and stroke<ref name="progesterone"/>
*[[Simvastatin]]: Administration in models of Parkinson's disease have been shown to have pronounced neuroprotective effects including anti-inflammatory effects due to NMDA receptor modulation<ref name="excitotoxic estrogen">{{cite journal | vauthors = Yan J, Xu Y, Zhu C, Zhang L, Wu A, Yang Y, Xiong Z, Deng C, Huang XF, Yenari MA, Yang YG, Ying W, Wang Q | title = Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses | journal = PLoS ONE | volume = 6 | issue = 6 | pages = e20945 | year = 2011 | pmid = 21731633 | pmc = 3120752 | doi = 10.1371/journal.pone.0020945 | editor1-last = Calixto | editor1-first = Joao B }}</ref>
*[[Memantine]]: As a low-affinity NMDA antagonist that is uncompetitive, memantine inhibits NMDA induced excitotoxicity while still preserving a degree of NMDA signalling.<ref>{{cite journal | vauthors = Volbracht C, van Beek J, Zhu C, Blomgren K, Leist M | title = Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity | journal = The European Journal of Neuroscience | volume = 23 | issue = 10 | pages = 2611–22 | date = May 2006 | pmid = 16817864 | doi = 10.1111/j.1460-9568.2006.04787.x | citeseerx = 10.1.1.574.474 }}</ref>
== Oxidative stress ==
== Mechanisms of Neuroprotection ==
{{main|Oxidative stress}}
Increased levels of oxidative stress can be caused in part by neuroinflammation, which is a highly recognized part of cerebral ischemia as well as many neurodegenerative diseases including [[Parkinson's disease]], [[Alzheimer's disease]], and [[Amyotrophic Lateral Sclerosis]].<ref name="oxidative stress"/><ref name="inflammation"/> The increased levels of oxidative stress are widely targeted in neuroprotective treatments because of their role in causing neuron apoptosis. Oxidative stress can directly cause neuron cell death or it can trigger a cascade of events that leads to protein misfolding, proteasomal malfunction, mitochondrial dysfunction, or glial cell activation.<ref name="overview of PD"/><ref name="prospects"/><ref name="oxidative stress"/><ref name="protein misfolding">{{cite journal |vauthors=Liu T, Bitan G | title = Modulating self-assembly of amyloidogenic proteins as a therapeutic approach for neurodegenerative diseases: strategies and mechanisms | journal = ChemMedChem | volume = 7 | issue = 3 | pages = 359–74 |date=March 2012 | pmid = 22323134 | doi = 10.1002/cmdc.201100585 }}</ref> If one of these events is triggered, further neurodegradation is caused as each of these events causes neuron cell apoptosis.<ref name="prospects"/><ref name="oxidative stress"/><ref name="protein misfolding"/> By decreasing oxidative stress through neuroprotective treatments, further neurodegradation can be inhibited.
=== Antioxidants ===
Neuroprotection involves a variety of mechanisms that can be broadly categorized into the following:
{{main|Antioxidants}}
Antioxidants are the primary treatment used to control oxidative stress levels. Antioxidants work to eliminate [[reactive oxygen species]], which are the prime cause of neurodegradation. The effectiveness of antioxidants in preventing further neurodegradation is not only disease dependent but can also depend on gender, ethnicity, and age. Listed below are common antioxidants shown to be effective in reducing oxidative stress in at least one neurodegenerative disease:
* [[Acetylcysteine]]: It targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways.<ref name="pmid23369637">{{cite journal |vauthors=Berk M, Malhi GS, Gray LJ, Dean OM | title = The promise of N-acetylcysteine in neuropsychiatry | journal = Trends Pharmacol. Sci. | volume = 34 | issue = 3 | pages = 167–77 | year = 2013 | pmid = 23369637 | doi = 10.1016/j.tips.2013.01.001 }}</ref><ref name="pmid23178231">{{cite journal |vauthors=Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M | title = Putative neuroprotective agents in neuropsychiatric disorders | journal = Prog. Neuropsychopharmacol. Biol. Psychiatry | volume = 42 | issue = | pages = 135–45 | year = 2013 | pmid = 23178231 | doi = 10.1016/j.pnpbp.2012.11.007 }}</ref>
=== Antioxidant Defense ===
* [[Crocin]]: Derived from [[saffron]], crocin has been shown to be a potent neuronal [[antioxidant]].<ref name="aggregation-Papandreou">{{cite journal |vauthors=Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, Lamari FN | title=Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents | journal=J Agric Food Chem | year=2006 | pages=8762–8 | volume=54 | issue=23 | pmid=17090119 | doi=10.1021/jf061932a}}</ref><ref name="carotenoids-Ochiai">{{cite journal |vauthors=Ochiai T, Shimeno H, Mishima K, Iwasaki K, Fujiwara M, Tanaka H, Shoyama Y, Toda A, Eyanagi R, Soeda S | title = Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo | journal = Biochim. Biophys. Acta | volume = 1770 | issue = 4 | pages = 578–84 | year = 2007 | pmid = 17215084 | doi = 10.1016/j.bbagen.2006.11.012 }}</ref><ref name="oxidativestress-Zheng">{{cite journal |vauthors=Zheng YQ, Liu JX, Wang JN, Xu L | title=Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia | journal=Brain Res. | year=2006 | pages=86–94 | volume=1138 | pmid=17274961 | doi=10.1016/j.brainres.2006.12.064}}</ref>
*Estrogen: [[17α-estradiol]] and [[17β-estradiol]] have been shown to be effective as antioxidants. The potential for these drugs is enormous. 17α-estradiol is the nonestrogenic stereoisomer of 17β-estradiol. The effectiveness of 17α-estradiol is important because it shows that the mechanism is dependent on the presence of the specific hydroxyl group, but independent of the activation of estrogen receptors. This means more antioxidants can be developed with bulky side chains so that they don't bind to the receptor but still possess the antioxidant properties.<ref name="estrogen">{{cite journal |vauthors=Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, Holsboer F | title = Neuroprotection against oxidative stress by estrogens: structure-activity relationship | journal = Mol. Pharmacol. | volume = 51 | issue = 4 | pages = 535–41 |date=April 1997 | pmid = 9106616 | doi = 10.1124/mol.51.4.535}}</ref>
*[[Fish oil]]: This contains n-3 polyunsaturated fatty acids that are known to offset oxidative stress and mitochondrial dysfunction. It has high potential for being neuroprotective and many studies are being done looking at the effects in neurodegenerative diseases<ref name="fish oil">{{cite journal |vauthors=Denny Joseph KM, Muralidhara M | title = Fish oil prophylaxis attenuates rotenone-induced oxidative impairments and mitochondrial dysfunctions in rat brain | journal = Food Chem. Toxicol. | volume = 50 | issue = 5 | pages = 1529–37 |date=May 2012 | pmid = 22289576 | doi = 10.1016/j.fct.2012.01.020 }}</ref>
*[[Minocycline]]: Minocycline is a semi-synthetic tetracycline compound that is capable of crossing the blood brain barrier. It is known to be a strong antioxidant and has broad anti-inflammatory properties. Minocyline has been shown to have neuroprotective activity in the CNS for Huntington's disease, Parkinson's disease, Alzheimer's disease, and ALS.<ref name="minocycline">{{cite journal |vauthors=Tikka TM, Koistinaho JE | title = Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia | journal = J. Immunol. | volume = 166 | issue = 12 | pages = 7527–33 |date=June 2001 | pmid = 11390507 | doi = 10.4049/jimmunol.166.12.7527}}</ref><ref name="minocycline2">{{cite journal |vauthors=Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK | title = Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice | journal = Brain Res. | volume = 1286 | issue = | pages = 174–84 |date=August 2009 | pmid = 19523933 | pmc = 3402231 | doi = 10.1016/j.brainres.2009.06.007 }}</ref>
*[[Pyrroloquinoline quinone|PQQ]]: Pyrroloquinoline quinone (PQQ) as an antioxidant has multiple modes of neuroprotection.<!--See main article for refs, although some can be duplicated here.-->
*[[Resveratrol]]: Resveratrol prevents oxidative stress by attenuating hydrogen peroxide-induced cytotoxicity and intracellular accumulation of ROS. It has been shown to exert protective effects in multiple neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ALS as well as in cerebral ischemia.<ref name="ND resveratrol">{{cite journal |vauthors=Yu W, Fu YC, Wang W | title = Cellular and molecular effects of resveratrol in health and disease | journal = J. Cell. Biochem. | volume = 113 | issue = 3 | pages = 752–9 |date=March 2012 | pmid = 22065601 | doi = 10.1002/jcb.23431 }}</ref><ref name="resveratrol2">{{cite journal |vauthors=Simão F, Matté A, Matté C, Soares FM, Wyse AT, Netto CA, Salbego CG | title = Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats | journal = J. Nutr. Biochem. | volume = 22 | issue = 10 | pages = 921–8 |date=October 2011 | pmid = 21208792 | doi = 10.1016/j.jnutbio.2010.07.013 }}</ref>
*[[Vinpocetine]]: Vinpocetine exerts neuroprotective effects in ischaemia of the brain through actions on cation channels, glutamate receptors and other pathways.<ref name="pmid24412512">{{cite journal |vauthors=Nivison-Smith L, Acosta ML, Misra S, O'Brien BJ, Kalloniatis M | title = Vinpocetine regulates cation channel permeability of inner retinal neurons in the ischaemic retina | journal = Neurochem. Int. | volume = 66C | issue = | pages = 1–14 | year = 2014 | pmid = 24412512 | doi = 10.1016/j.neuint.2014.01.003 }}</ref> The drop in dopamine produced by vinpocetine may contribute to its protective action from oxidative damage, particularly in dopamine-rich structures.<ref name="pmid23121080">{{cite journal |vauthors=Herrera-Mundo N, Sitges M | title = Vinpocetine and α-tocopherol prevent the increase in DA and oxidative stress induced by 3-NPA in striatum isolated nerve endings | journal = J. Neurochem. | volume = 124 | issue = 2 | pages = 233–40 | year = 2013 | pmid = 23121080 | doi = 10.1111/jnc.12082 }}</ref> Vinpocetine as a unique anti-inflammatory agent may be beneficial for the treatment of neuroinflammatory diseases.<ref name="pmid22874716">{{cite journal |vauthors=Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG | title = TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation | journal = Neuron Glia Biol. | volume = 7 | issue = 2–4 | pages = 187–97 | year = 2011 | pmid = 22874716 | doi = 10.1017/S1740925X12000129 }}</ref> It increases cerebral blood flow and oxygenation.<ref name="pmid12044859">{{cite journal |vauthors=Bönöczk P, Panczel G, Nagy Z | title = Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study | journal = Eur J Ultrasound | volume = 15 | issue = 1–2 | pages = 85–91 | year = 2002 | pmid = 12044859 | doi = 10.1016/s0929-8266(02)00006-x}}</ref>
*[[THC]]: Delta 9-tetrahydrocannabinol exerts neuroprotective and antioxidative effects by inhibiting [[NMDA]] neurotoxicity in neuronal cultures exposed to toxic levels of the neurotransmitter, glutamate.<ref name="pmid10863546">{{cite journal |vauthors = Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J |title=Neuroprotective antioxidants from marijuana |journal = Ann. N. Y. Acad. Sci. |volume = 899 |issue= |pages = 274–82 |year = 2000 |pmid = 10863546 |doi=10.1111/j.1749-6632.2000.tb06193.x }}</ref>
*[[Vitamin E]]: Vitamin E has had varying responses as an antioxidant depending on the neurodegenerative disease that it is being treated. It is most effective in Alzheimer's disease and has been shown to have questionable neuroprotection effects when treating ALS. A meta-analysis involving 135,967 participants showed there is a significant relationship between vitamin E dosage and all-cause mortality, with dosages equal to or greater than 400 IU per day showing an increase in all-cause mortality. However, there is a decrease in all-cause mortality at lower doses, optimum being 150 IU per day.<ref name="PMID 15537682">{{cite journal | vauthors = ((Miller ER 3rd)), Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E | title = Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. | journal = Ann Intern Med | volume = 142 | issue = 1 | pages = 37–46 | year = 2005 | pmid = 15537682 | doi=10.7326/0003-4819-142-1-200501040-00110}}</ref> Vitamin E is ineffective for neuroprotection in Parkinson's disease.<ref name="prospects"/><ref name="oxidative stress"/>
== Stimulants ==
Oxidative stress is a major contributor to neuronal damage. Antioxidants help to neutralize [[free radicals]] and reduce oxidative stress, thereby protecting neurons. Common antioxidants include [[vitamin E]], [[vitamin C]], and [[glutathione]].
[[NMDA receptor]] stimulants can lead to glutamate and calcium [[excitotoxicity]] and [[neuroinflammation]]. Some other stimulants, in appropriate doses, can however be neuroprotective.
*[[Selegiline]]: It has been shown to slow early progression of Parkinson's disease and delayed the emergence of disability by an average of nine months.<ref name="prospects"/>
=== Anti-inflammatory Agents ===
* [[Nicotine]]: It has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.<ref name="pmid10857708">{{cite journal |vauthors=Kelton MC, Kahn HJ, Conrath CL, Newhouse PA | title = The effects of nicotine on Parkinson's disease | journal = Brain Cogn | volume = 43 | issue = 1–3 | pages = 274–82 | year = 2000 | pmid = 10857708 | doi = }}</ref><ref name="Ross_2001">{{cite journal |vauthors=Ross GW, Petrovitch H | title = Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease | journal = Drugs Aging | volume = 18 | issue = 11 | pages = 797–806 | year = 2001 | pmid = 11772120 | doi = 10.2165/00002512-200118110-00001}}</ref><ref name="pmid25620929">{{cite journal | vauthors = Barreto GE, Iarkov A, Moran VE | title = Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease | journal = Frontiers in Aging Neuroscience | volume = 6 | issue = | pages = 340 | date = 2014 | pmid = 25620929 | pmc = 4288130 | doi = 10.3389/fnagi.2014.00340 }}</ref>
* [[Caffeine]]: It is protective against Parkinson's disease.<ref name="Ross_2001"/><ref name="pmid20167258">{{cite journal |vauthors=Xu K, Xu YH, Chen JF, Schwarzschild MA | title = Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson's disease | journal = Neuroscience | volume = 167 | issue = 2 | pages = 475–81 | year = 2010 | pmid = 20167258 | pmc = 2849921 | doi = 10.1016/j.neuroscience.2010.02.020 }}</ref> Caffeine induces neuronal glutathione synthesis by promoting cysteine uptake, leading to neuroprotection.<ref name="pmid21371533">{{cite journal |vauthors=Aoyama K, Matsumura N, Watabe M, Wang F, Kikuchi-Utsumi K, Nakaki T | title = Caffeine and uric acid mediate glutathione synthesis for neuroprotection | journal = Neuroscience | volume = 181 | issue = | pages = 206–15 | year = 2011 | pmid = 21371533 | doi = 10.1016/j.neuroscience.2011.02.047 }}</ref>
== Other neuroprotective treatments==
Inflammation is a response to injury that can exacerbate neuronal damage. Anti-inflammatory agents, such as [[non-steroidal anti-inflammatory drugs]] (NSAIDs) and [[corticosteroids]], can help reduce inflammation and protect neurons.
More neuroprotective treatment options exist that target different mechanisms of neurodegradation. Continued research is being done in an effort to find any method effective in preventing the onset or progression of neurodegenerative diseases or secondary injuries. These include:
*[[Caspase]] inhibitors: These are primarily used and studied for their anti [[apoptosis|apoptotic]] effects.<ref name="capase">{{cite journal |vauthors=Li W, Lee MK | title = Antiapoptotic property of human alpha-synuclein in neuronal cell lines is associated with the inhibition of caspase-3 but not caspase-9 activity | journal = J. Neurochem. | volume = 93 | issue = 6 | pages = 1542–50 |date=June 2005 | pmid = 15935070 | doi = 10.1111/j.1471-4159.2005.03146.x }}</ref>
*[[Growth factor|Trophic factors]]: The use of trophic factors for neuroprotection in CNS disorders is being explored, specifically in ALS. Potentially neuroprotective trophic factors include [[CNTF]], [[IGF-1]], [[VEGF]], and [[BDNF]]<ref name="trophic factors">{{cite journal |vauthors=Gunasekaran R, Narayani RS, Vijayalakshmi K, Alladi PA, Shobha K, Nalini A, Sathyaprabha TN, Raju TR | title = Exposure to cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients alters Nav1.6 and Kv1.6 channel expression in rat spinal motor neurons | journal = Brain Res. | volume = 1255 | issue = | pages = 170–9 |date=February 2009 | pmid = 19109933 | doi = 10.1016/j.brainres.2008.11.099 }}</ref>
*[[Therapeutic hypothermia]]: This is being explored as a neuroprotection treatment option for patients with traumatic brain injury and is suspected to help reduce intracranial pressure.<ref name="hypothermia">{{cite journal |vauthors=Sinclair HL, Andrews PJ | title = Bench-to-bedside review: Hypothermia in traumatic brain injury | journal = Crit Care | volume = 14 | issue = 1 | pages = 204 | year = 2010 | pmid = 20236503 | pmc = 2875496 | doi = 10.1186/cc8220 }}</ref>
* [[Erythropoietin]] has been reported to protect nerve cells from [[hypoxia (medical)|hypoxia]]-induced [[glutamate toxicity]] (see [[erythropoietin in neuroprotection]]).
* [[Lithium (medication)|Lithium]] exerts neuroprotective effects and stimulates neurogenesis via multiple signaling pathways; it inhibits glycogen synthase kinase-3 (GSK-3), upregulates neurotrophins and growth factors (e.g., brain-derived neurotrophic factor (BDNF)), modulates inflammatory molecules, upregulates neuroprotective factors (e.g., B-cell lymphoma-2 (Bcl-2), heat shock protein 70 (HSP-70)), and concomitantly downregulates pro-apoptotic factors. Lithium has been shown to reduce neuronal death, microglial activation, cyclooxygenase-2 induction, amyloid-β (Aβ), and hyperphosphorylated tau levels, to preserve blood-brain barrier integrity, to mitigate neurological deficits and psychiatric disturbance, and to improve learning and memory outcome.<ref>{{cite journal|doi=10.1021/cn500040g | pmid=24697257 | pmc=4063503 | volume=5 | issue=6 | title=A New Avenue for Lithium: Intervention in Traumatic Brain Injury | year=2014 | journal=ACS Chemical Neuroscience | pages=422–433 | vauthors = Leeds PR, Yu F, Wang Z, ((Chiu C-T)), Zhang Y, Leng Y, Linares GR, ((Chuang D-M))}}</ref>
* [[Neuroprotectin D1]] and other neuroprotectins (see [[specialized proresolving mediators#DHA-derived protectins/neuroprotectins]]) and certain [[resolvin]]s of the D series (i.e. RvD1, RvD2, RvD3, RvD4, RvD5, and RvD6; see [[specialized proresolving mediators#DHA-derived Resolvins]]) are [[docosanoid]] metabolites of the [[omega 3 fatty acid]], [[docosahexaenoic acid]] (DHA) while resolvins of the E series (RvD1, RvD2, and RvD3; see [[specialized proresolving mediators#EPA-derived resolvins (i.e. RvE)]]) are [[eicosanoid]] metabolites of the omega 3 fatty acid, [[eicosapentaenoic acid]] (EPA). These metabolites, which are made by the action of cellular [[lipoxygenase]], [[cyclooxygenase]], and/or [[cytochrome P450]] enzymes on DHA or EPA, have been shown to have potent anti-[[inflammation]] activity and to be neuroprotective in various models of inflammation-involving neurological diseases such as various degenerative diseases including Alzheimer's disease.<ref name="pmid16897369">{{cite journal | vauthors = Bazan NG |authorlink1=Nicolas Bazan | title = The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling | journal = Cellular and Molecular Neurobiology | volume = 26 | issue = 4–6 | pages = 901–13 | year = 2006 | pmid = 16897369 | doi = 10.1007/s10571-006-9064-6 }}</ref><ref name="pmid25792098">{{cite journal | vauthors = Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP | title = Neuroinflammation in Alzheimer's disease | journal = The Lancet. Neurology | volume = 14 | issue = 4 | pages = 388–405 | year = 2015 | pmid = 25792098 | pmc = 5909703 | doi = 10.1016/S1474-4422(15)70016-5 }}</ref> A metabolically resistant analog of RvE1 is in development for the treatment of retinal disease and neuroprotectin D1 mimetics are in development for treatment of neurodegenerative diseases and hearing loss.<ref name="pmid25857211">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–15 | year = 2015 | pmid = 25857211 | pmc = 4515371 | doi = 10.1016/j.smim.2015.03.004 }}</ref>
==See also==
=== Excitotoxicity Inhibition ===
* [[Neurodegeneration]]
* [[Neuroregeneration]]
== References ==
[[Excitotoxicity]] occurs when neurons are damaged and killed by excessive stimulation by neurotransmitters such as [[glutamate]]. Neuroprotective strategies aim to inhibit excitotoxicity by blocking glutamate receptors or reducing glutamate release.
{{Reflist}}
== Further reading ==
=== Neurotrophic Factors ===
===Articles===
[[Neurotrophic factors]] are proteins that support the growth, survival, and differentiation of neurons. Examples include [[nerve growth factor]] (NGF) and [[brain-derived neurotrophic factor]] (BDNF). These factors can be used to promote neuronal survival and repair.
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* {{cite journal | vauthors = Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M | title = Putative neuroprotective agents in neuropsychiatric disorders | journal = Progress in Neuro-psychopharmacology & Biological Psychiatry | volume = 42 | issue = | pages = 135–45 | year = 2013 | pmid = 23178231 | doi = 10.1016/j.pnpbp.2012.11.007 | url = https://www.researchgate.net/publication/233768271 | accessdate = 2016-01-03}}
* {{cite journal | vauthors = Venkatesan R, Ji E, Kim SY | title = Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review | journal = BioMed Research International | volume = 2015 | issue = | pages = 1–22 | year = 2015 | pmid = 26075266 | pmc = 4446472 | doi = 10.1155/2015/814068 }}
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===Books===
== Applications of Neuroprotection ==
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* {{cite book | first = Kewal K. | last = Jain | name-list-format = vanc | title = The Handbook of Neuroprotection | publisher = Humana Press | location = Totowa, NJ | year = 2011 | pages = | isbn = 978-1-61779-048-5 | oclc = | doi = | accessdate = }}
* {{cite book | first = Tiziana | last = Borsello | name-list-format = vanc | title = Neuroprotection Methods and Protocols (Methods in Molecular Biology) | publisher = Humana Press | location = Totowa, NJ | year = 2007 | origyear = | pages = 239 | quote = | isbn = 978-1-58829-666-5 | url-access = registration | url = https://archive.org/details/neuroprotectionm00bors }}
* {{cite book | first = Christian | last = Alzheimer | name-list-format = vanc | title = Molecular and cellular biology of neuroprotection in the CNS | publisher = Kluwer Academic / Plenum Publishers | location = New York | year = 2002 | pages = | isbn = 978-0-306-47414-9 | oclc = | doi = | accessdate = }}
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Neuroprotection is a critical area of research in the treatment of various neurological conditions, including:
=== Stroke ===
In the case of [[ischemic stroke]], neuroprotective strategies aim to reduce the extent of brain damage by preserving neuronal function and preventing cell death.
=== Alzheimer's Disease ===
Neuroprotective approaches in [[Alzheimer's disease]] focus on reducing amyloid-beta accumulation, tau phosphorylation, and oxidative stress to slow disease progression.
=== Parkinson's Disease ===
In [[Parkinson's disease]], neuroprotection aims to preserve dopaminergic neurons in the [[substantia nigra]] and reduce oxidative stress and inflammation.
== Challenges and Future Directions ==
Despite significant research, effective neuroprotective therapies remain limited. Challenges include the complexity of the nervous system, the difficulty in delivering drugs across the [[blood-brain barrier]], and the need for early intervention. Future research is focused on developing more targeted therapies and improving drug delivery methods.
Neuroprotection refers to the mechanisms and strategies used to protect the nervous system from injury and degeneration. The primary goal of neuroprotection is to prevent or slow the progression of neurodegenerative diseases and to limit the extent of damage following neurological injury.
Oxidative stress is a major contributor to neuronal damage. Antioxidants help to neutralize free radicals and reduce oxidative stress, thereby protecting neurons. Common antioxidants include vitamin E, vitamin C, and glutathione.
Inflammation is a response to injury that can exacerbate neuronal damage. Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, can help reduce inflammation and protect neurons.
Excitotoxicity occurs when neurons are damaged and killed by excessive stimulation by neurotransmitters such as glutamate. Neuroprotective strategies aim to inhibit excitotoxicity by blocking glutamate receptors or reducing glutamate release.
In the case of ischemic stroke, neuroprotective strategies aim to reduce the extent of brain damage by preserving neuronal function and preventing cell death.
Neuroprotective approaches in Alzheimer's disease focus on reducing amyloid-beta accumulation, tau phosphorylation, and oxidative stress to slow disease progression.
Despite significant research, effective neuroprotective therapies remain limited. Challenges include the complexity of the nervous system, the difficulty in delivering drugs across the blood-brain barrier, and the need for early intervention. Future research is focused on developing more targeted therapies and improving drug delivery methods.
