Neuroprotection

Neuroprotection refers to the relative preservation of neuronal structure and/or function.[1] 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.[1] 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.[2] Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation.[3][2][4][5] 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.[6] Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

Excitotoxicity
Main article: 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 receptors, allows for an increase in calcium ion (Ca2+) influx due to the lack of specificity in the ion channel opened upon glutamate binding.[6][7] As Ca2+ accumulates in the neuron, the buffering levels of mitochondrial Ca2+ sequestration are exceeded, which has major consequences for the neuron.[6] Because Ca2+ is a secondary messenger and regulates a large number of downstream processes, accumulation of Ca2+ causes improper regulation of these processes, eventually leading to cell death.[8][9][10] Ca2+ is also thought to trigger neuroinflammation, a key component in all CNS disorders.[6]

Glutamate antagonists

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 receptors such that accumulation of Ca2+ 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: 17β-Estradiol helps regulate excitotoxicity by inhibiting NMDA receptors as well as other glutamate receptors.[11]
  • 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.[7]
  • Progesterone: Administration of progesterone is well known to aid in the prevention of secondary injuries in patients with traumatic brain injury and stroke.[10]
  • 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.[12]
  • Memantine: As a low-affinity NMDA antagonist that is uncompetitive, memantine inhibits NMDA induced excitotoxicity while still preserving a degree of NMDA signalling.[13]
  • Riluzole is an antiglutamatergic drug used to slow the progression of amyotrophic lateral sclerosis.

Oxidative stress
Main article: 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.[5][6] 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.[2][4][5][14] If one of these events is triggered, further neurodegradation is caused as each of these events causes neuron cell apoptosis.[4][5][14] By decreasing oxidative stress through neuroprotective treatments, further neurodegradation can be inhibited.

Antioxidants
Main article: 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.[15][16]
  • Crocin: Derived from saffron, crocin has been shown to be a potent neuronal antioxidant.[17][18][19]
  • 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.[20]
  • 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[21]
  • 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.[22][23]
  • PQQ: Pyrroloquinoline quinone (PQQ) as an antioxidant has multiple modes of neuroprotection.
  • 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.[24][25]
  • Vinpocetine: Vinpocetine exerts neuroprotective effects in ischaemia of the brain through actions on cation channels, glutamate receptors and other pathways.[26] The drop in dopamine produced by vinpocetine may contribute to its protective action from oxidative damage, particularly in dopamine-rich structures.[27] Vinpocetine as a unique anti-inflammatory agent may be beneficial for the treatment of neuroinflammatory diseases.[28] It increases cerebral blood flow and oxygenation.[29]
  • THC: Delta 9-tetrahydrocannabinol exerts neuroprotective and antioxidative effects by inhibiting NMDA neurotoxicity in neuronal cultures exposed to toxic levels of the neurotransmitter, glutamate.[30]
  • 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.[31] Vitamin E is ineffective for neuroprotection in Parkinson's disease.[4][5]

Stimulants

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.[4]
  • Nicotine: It has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.[32][33][34]
  • Caffeine: It is protective against Parkinson's disease.[33][35] Caffeine induces neuronal glutathione synthesis by promoting cysteine uptake, leading to neuroprotection.[36]

Neuroprotectants (cerebroprotectants) for acute ischemic stroke

When applied to protecting the brain from the effects of acute ischemic stroke, neuroprotectants are often called cerebroprotectants. Over 150 drugs have been tested in clinical trials, leading to the regulatory approval of tissue plasminogen activator in several countries, the and approval of edaravone in Japan.

Other neuroprotective treatments

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:

See also

References
  1. Casson RJ, Chidlow G, Ebneter A, Wood JP, Crowston J, Goldberg I (2012). "Translational neuroprotection research in glaucoma: a review of definitions and principles". Clinical & Experimental Ophthalmology. 40 (4): 350–357. doi:10.1111/j.1442-9071.2011.02563.x. PMID 22697056.
  2. Seidl SE, Potashkin JA (2011). "The promise of neuroprotective agents in Parkinson's disease". Frontiers in Neurology. 2: 68. doi:10.3389/fneur.2011.00068. PMC 3221408. PMID 22125548.
  3. Kaur H, Prakash A, Medhi B (2013). "Drug therapy in stroke: from preclinical to clinical studies". Pharmacology. 92 (5–6): 324–334. doi:10.1159/000356320. PMID 24356194.
  4. Dunnett SB, Björklund A (June 1999). "Prospects for new restorative and neuroprotective treatments in Parkinson's disease". Nature. 399 (6738 Suppl): A32–A39. doi:10.1038/399a032. PMID 10392578. S2CID 17462928.
  5. Andersen JK (July 2004). "Oxidative stress in neurodegeneration: cause or consequence?". Nature Medicine. 10 Suppl (7): S18–S25. doi:10.1038/nrn1434. PMID 15298006. S2CID 9569296.
  6. Zádori D, Klivényi P, Szalárdy L, Fülöp F, Toldi J, Vécsei L (November 2012). "Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: novel therapeutic strategies for neurodegenerative disorders". Journal of the Neurological Sciences. 322 (1–2): 187–191. doi:10.1016/j.jns.2012.06.004. PMID 22749004. S2CID 25867213.
  7. Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, et al. (January 2012). "Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting ca(2+) influx". Cellular and Molecular Neurobiology. 32 (1): 121–128. doi:10.1007/s10571-011-9742-x. PMID 21811848. S2CID 17935161.
  8. Sattler R, Tymianski M (2000). "Molecular mechanisms of calcium-dependent excitotoxicity". Journal of Molecular Medicine. 78 (1): 3–13. doi:10.1007/s001090000077. PMID 10759025. S2CID 20740220.
  9. Sattler R, Tymianski M (2001). "Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death". Molecular Neurobiology. 24 (1–3): 107–129. doi:10.1385/MN:24:1-3:107. PMID 11831548. S2CID 23999220.
  10. Luoma JI, Stern CM, Mermelstein PG (August 2012). "Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection". The Journal of Steroid Biochemistry and Molecular Biology. 131 (1–2): 30–36. doi:10.1016/j.jsbmb.2011.11.002. PMC 3303940. PMID 22101209.
  11. Liu SB, Zhang N, Guo YY, Zhao R, Shi TY, Feng SF, et al. (April 2012). "G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors". The Journal of Neuroscience. 32 (14): 4887–4900. doi:10.1523/JNEUROSCI.5828-11.2012. PMC 6620914. PMID 22492045.
  12. Yan J, Xu Y, Zhu C, Zhang L, Wu A, Yang Y, et al. (2011). Calixto JB (ed.). "Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses". PLOS ONE. 6 (6): e20945. Bibcode:2011PLoSO...620945Y. doi:10.1371/journal.pone.0020945. PMC 3120752. PMID 21731633.
  13. Volbracht C, van Beek J, Zhu C, Blomgren K, Leist M (May 2006). "Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity". The European Journal of Neuroscience. 23 (10): 2611–2622. CiteSeerX 10.1.1.574.474. doi:10.1111/j.1460-9568.2006.04787.x. PMID 16817864. S2CID 14461534.
  14. Liu T, Bitan G (March 2012). "Modulating self-assembly of amyloidogenic proteins as a therapeutic approach for neurodegenerative diseases: strategies and mechanisms". ChemMedChem. 7 (3): 359–374. doi:10.1002/cmdc.201100585. PMID 22323134. S2CID 14427130.
  15. Berk M, Malhi GS, Gray LJ, Dean OM (March 2013). "The promise of N-acetylcysteine in neuropsychiatry". Trends in Pharmacological Sciences. 34 (3): 167–177. doi:10.1016/j.tips.2013.01.001. PMID 23369637.
  16. Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M (April 2013). "Putative neuroprotective agents in neuropsychiatric disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 42: 135–145. doi:10.1016/j.pnpbp.2012.11.007. hdl:11343/43868. PMID 23178231. S2CID 6678887.
  17. Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, Lamari FN (November 2006). "Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents". Journal of Agricultural and Food Chemistry. 54 (23): 8762–8768. doi:10.1021/jf061932a. PMID 17090119.
  18. Ochiai T, Shimeno H, Mishima K, Iwasaki K, Fujiwara M, Tanaka H, et al. (April 2007). "Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (4): 578–584. doi:10.1016/j.bbagen.2006.11.012. PMID 17215084.
  19. Zheng YQ, Liu JX, Wang JN, Xu L (March 2007). "Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia". Brain Research. 1138: 86–94. doi:10.1016/j.brainres.2006.12.064. PMID 17274961. S2CID 25495517.
  20. Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, Holsboer F (April 1997). "Neuroprotection against oxidative stress by estrogens: structure-activity relationship". Molecular Pharmacology. 51 (4): 535–541. doi:10.1124/mol.51.4.535. PMID 9106616. S2CID 1197332.
  21. Denny Joseph KM, Muralidhara M (May 2012). "Fish oil prophylaxis attenuates rotenone-induced oxidative impairments and mitochondrial dysfunctions in rat brain". Food and Chemical Toxicology. 50 (5): 1529–1537. doi:10.1016/j.fct.2012.01.020. PMID 22289576.
  22. Tikka TM, Koistinaho JE (June 2001). "Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia". Journal of Immunology. 166 (12): 7527–7533. doi:10.4049/jimmunol.166.12.7527. PMID 11390507.
  23. Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK (August 2009). "Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice". Brain Research. 1286: 174–184. doi:10.1016/j.brainres.2009.06.007. PMC 3402231. PMID 19523933.
  24. Yu W, Fu YC, Wang W (March 2012). "Cellular and molecular effects of resveratrol in health and disease". Journal of Cellular Biochemistry. 113 (3): 752–759. doi:10.1002/jcb.23431. PMID 22065601. S2CID 26185378.
  25. Simão F, Matté A, Matté C, Soares FM, Wyse AT, Netto CA, Salbego CG (October 2011). "Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats". The Journal of Nutritional Biochemistry. 22 (10): 921–928. doi:10.1016/j.jnutbio.2010.07.013. PMID 21208792.
  26. Nivison-Smith L, Acosta ML, Misra S, O'Brien BJ, Kalloniatis M (January 2014). "Vinpocetine regulates cation channel permeability of inner retinal neurons in the ischaemic retina". Neurochemistry International. 66: 1–14. doi:10.1016/j.neuint.2014.01.003. PMID 24412512. S2CID 27208165.
  27. Herrera-Mundo N, Sitges M (January 2013). "Vinpocetine and α-tocopherol prevent the increase in DA and oxidative stress induced by 3-NPA in striatum isolated nerve endings". Journal of Neurochemistry. 124 (2): 233–240. doi:10.1111/jnc.12082. PMID 23121080.
  28. Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG (May 2011). "TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation". Neuron Glia Biology. 7 (2–4): 187–197. doi:10.1017/S1740925X12000129. PMID 22874716.
  29. Bönöczk P, Panczel G, Nagy Z (June 2002). "Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study". European Journal of Ultrasound. 15 (1–2): 85–91. doi:10.1016/s0929-8266(02)00006-x. PMID 12044859.
  30. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J (2000). "Neuroprotective antioxidants from marijuana". Annals of the New York Academy of Sciences. 899 (1): 274–282. Bibcode:2000NYASA.899..274H. doi:10.1111/j.1749-6632.2000.tb06193.x. PMID 10863546. S2CID 39496546.
  31. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (January 2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality". Annals of Internal Medicine. 142 (1): 37–46. doi:10.7326/0003-4819-142-1-200501040-00110. PMID 15537682.
  32. Kelton MC, Kahn HJ, Conrath CL, Newhouse PA (2000). "The effects of nicotine on Parkinson's disease". Brain and Cognition. 43 (1–3): 274–282. PMID 10857708.
  33. Ross GW, Petrovitch H (2001). "Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease". Drugs & Aging. 18 (11): 797–806. doi:10.2165/00002512-200118110-00001. PMID 11772120. S2CID 23840476.
  34. Barreto GE, Iarkov A, Moran VE (2014). "Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease". Frontiers in Aging Neuroscience. 6: 340. doi:10.3389/fnagi.2014.00340. PMC 4288130. PMID 25620929.
  35. Xu K, Xu YH, Chen JF, Schwarzschild MA (May 2010). "Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson's disease". Neuroscience. 167 (2): 475–481. doi:10.1016/j.neuroscience.2010.02.020. PMC 2849921. PMID 20167258.
  36. Aoyama K, Matsumura N, Watabe M, Wang F, Kikuchi-Utsumi K, Nakaki T (May 2011). "Caffeine and uric acid mediate glutathione synthesis for neuroprotection". Neuroscience. 181: 206–215. doi:10.1016/j.neuroscience.2011.02.047. PMID 21371533. S2CID 32651665.
  37. Li W, Lee MK (June 2005). "Antiapoptotic property of human alpha-synuclein in neuronal cell lines is associated with the inhibition of caspase-3 but not caspase-9 activity". Journal of Neurochemistry. 93 (6): 1542–1550. doi:10.1111/j.1471-4159.2005.03146.x. PMID 15935070.
  38. Gunasekaran R, Narayani RS, Vijayalakshmi K, Alladi PA, Shobha K, Nalini A, et al. (February 2009). "Exposure to cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients alters Nav1.6 and Kv1.6 channel expression in rat spinal motor neurons". Brain Research. 1255: 170–179. doi:10.1016/j.brainres.2008.11.099. PMID 19109933. S2CID 38399661.
  39. Sinclair HL, Andrews PJ (2010). "Bench-to-bedside review: Hypothermia in traumatic brain injury". Critical Care. 14 (1): 204. doi:10.1186/cc8220. PMC 2875496. PMID 20236503.
  40. Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, et al. (June 2014). "A new avenue for lithium: intervention in traumatic brain injury". ACS Chemical Neuroscience. 5 (6): 422–433. doi:10.1021/cn500040g. PMC 4063503. PMID 24697257.
  41. Bazan NG (2006). "The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling". Cellular and Molecular Neurobiology. 26 (4–6): 901–913. doi:10.1007/s10571-006-9064-6. PMID 16897369. S2CID 6059884.
  42. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. (April 2015). "Neuroinflammation in Alzheimer's disease". The Lancet. Neurology. 14 (4): 388–405. doi:10.1016/S1474-4422(15)70016-5. PMC 5909703. PMID 25792098.
  43. Serhan CN, Chiang N, Dalli J (May 2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology. 27 (3): 200–215. doi:10.1016/j.smim.2015.03.004. PMC 4515371. PMID 25857211.

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