Neuroprotection refers to the relative preservation of neuronal structure and/or function. 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. 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. 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. 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. 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.
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. As Ca2+ accumulates in the neuron, the buffering levels of mitochondrial Ca2+ sequestration are exceeded, which has major consequences for the neuron. 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. Ca2+ is also thought to trigger neuroinflammation, a key component in all CNS disorders
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.
- 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
- Progesterone: Administration of progesterone is well known to aid in the prevention of secondary injuries in patients with traumatic brain injury and stroke
- 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
- Memantine: As a low-affinity NMDA antagonist that is uncompetitive, memantine inhibits NMDA induced excitotoxicity while still preserving a degree of NMDA signalling.
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. 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. If one of these events is triggered, further neurodegradation is caused as each of these events causes neuron cell apoptosis. By decreasing oxidative stress through neuroprotective treatments, further neurodegradation can be inhibited.
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.
- Crocin: Derived from saffron, crocin has been shown to be a potent neuronal antioxidant.
- 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.
- 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
- 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.
- 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.
- Vinpocetine: Vinpocetine exerts neuroprotective effects in ischaemia of the brain through actions on cation channels, glutamate receptors and other pathways. The drop in dopamine produced by vinpocetine may contribute to its protective action from oxidative damage, particularly in dopamine-rich structures. Vinpocetine as a unique anti-inflammatory agent may be beneficial for the treatment of neuroinflammatory diseases. It increases cerebral blood flow and oxygenation.
- THC: Delta 9-tetrahydrocannabinol exerts neuroprotective and antioxidative effects by inhibiting NMDA neurotoxicity in neuronal cultures exposed to toxic levels of the neurotransmitter, glutamate.
- 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. Vitamin E is ineffective for neuroprotection in Parkinson's disease.
- 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.
- Nicotine: It has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.
- Caffeine: It is protective against Parkinson's disease. Caffeine induces neuronal glutathione synthesis by promoting cysteine uptake, leading to neuroprotection.
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:
- Caspase inhibitors: These are primarily used and studied for their anti apoptotic effects.
- 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
- 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.
- Erythropoietin has been reported to protect nerve cells from hypoxia-induced glutamate toxicity (see erythropoietin in neuroprotection).
- 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.
- Neuroprotectin D1 and other neuroprotectins (see specialized proresolving mediators#DHA-derived protectins/neuroprotectins) and certain resolvins 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. 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.
- Casson RJ, Chidlow G, Ebneter A, Wood JP, Crowston J, Goldberg I (2012). "Translational neuroprotection research in glaucoma: a review of definitions and principles". Clin. Experiment. Ophthalmol. 40 (4): 350–7. doi:10.1111/j.1442-9071.2011.02563.x. PMID 22697056.
- Seidl SE, Potashkin JA (2011). "The promise of neuroprotective agents in Parkinson's disease". Front Neurol. 2: 68. doi:10.3389/fneur.2011.00068. PMC 3221408. PMID 22125548.
- Dunnett SB, Björklund A (June 1999). "Prospects for new restorative and neuroprotective treatments in Parkinson's disease". Nature. 399 (6738 Suppl): A32–9. doi:10.1038/399a032. PMID 10392578.
- Andersen JK (July 2004). "Oxidative stress in neurodegeneration: cause or consequence?". Nat. Med. 10 Suppl (7): S18–25. doi:10.1038/nrn1434. PMID 15298006.
- Zádori D, Klivényi P, Szalárdy L, Fülöp F, Toldi J, Vécsei L (June 2012). "Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders". J Neurol Sci. 322 (1–2): 187–91. doi:10.1016/j.jns.2012.06.004. PMID 22749004.
- Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, Ma L, Cao R, Rao Z, Zhao G (January 2012). "Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting ca(2+) influx". Cell. Mol. Neurobiol. 32 (1): 121–8. doi:10.1007/s10571-011-9742-x. PMID 21811848.
- Sattler R, Tymianski M (2000). "Molecular mechanisms of calcium-dependent excitotoxicity". J. Mol. Med. 78 (1): 3–13. doi:10.1007/s001090000077. PMID 10759025.
- Sattler R, Tymianski M (2001). "Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death". Mol. Neurobiol. 24 (1–3): 107–29. doi:10.1385/MN:24:1-3:107. PMID 11831548.
- Luoma JI, Stern CM, Mermelstein PG (August 2012). "Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection". J. Steroid Biochem. Mol. Biol. 131 (1–2): 30–6. doi:10.1016/j.jsbmb.2011.11.002. PMC 3303940. PMID 22101209.
- 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 (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): 4887–900. doi:10.1523/JNEUROSCI.5828-11.2012. PMID 22492045.
- 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 (2011). Calixto JB (ed.). "Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses". PLoS ONE. 6 (6): e20945. doi:10.1371/journal.pone.0020945. PMC 3120752. PMID 21731633.
- 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): 2611–22. CiteSeerX 10.1.1.574.474. doi:10.1111/j.1460-9568.2006.04787.x. PMID 16817864.
- 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): 359–74. doi:10.1002/cmdc.201100585. PMID 22323134.
- Berk M, Malhi GS, Gray LJ, Dean OM (2013). "The promise of N-acetylcysteine in neuropsychiatry". Trends Pharmacol. Sci. 34 (3): 167–77. doi:10.1016/j.tips.2013.01.001. PMID 23369637.
- Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M (2013). "Putative neuroprotective agents in neuropsychiatric disorders". Prog. Neuropsychopharmacol. Biol. Psychiatry. 42: 135–45. doi:10.1016/j.pnpbp.2012.11.007. PMID 23178231.
- Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, Lamari FN (2006). "Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents". J Agric Food Chem. 54 (23): 8762–8. doi:10.1021/jf061932a. PMID 17090119.
- Ochiai T, Shimeno H, Mishima K, Iwasaki K, Fujiwara M, Tanaka H, Shoyama Y, Toda A, Eyanagi R, Soeda S (2007). "Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo". Biochim. Biophys. Acta. 1770 (4): 578–84. doi:10.1016/j.bbagen.2006.11.012. PMID 17215084.
- Zheng YQ, Liu JX, Wang JN, Xu L (2006). "Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia". Brain Res. 1138: 86–94. doi:10.1016/j.brainres.2006.12.064. PMID 17274961.
- 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". Mol. Pharmacol. 51 (4): 535–41. doi:10.1124/mol.51.4.535. PMID 9106616.
- Denny Joseph KM, Muralidhara M (May 2012). "Fish oil prophylaxis attenuates rotenone-induced oxidative impairments and mitochondrial dysfunctions in rat brain". Food Chem. Toxicol. 50 (5): 1529–37. doi:10.1016/j.fct.2012.01.020. PMID 22289576.
- Tikka TM, Koistinaho JE (June 2001). "Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia". J. Immunol. 166 (12): 7527–33. doi:10.4049/jimmunol.166.12.7527. PMID 11390507.
- 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 Res. 1286: 174–84. doi:10.1016/j.brainres.2009.06.007. PMC 3402231. PMID 19523933.
- Yu W, Fu YC, Wang W (March 2012). "Cellular and molecular effects of resveratrol in health and disease". J. Cell. Biochem. 113 (3): 752–9. doi:10.1002/jcb.23431. PMID 22065601.
- 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". J. Nutr. Biochem. 22 (10): 921–8. doi:10.1016/j.jnutbio.2010.07.013. PMID 21208792.
- Nivison-Smith L, Acosta ML, Misra S, O'Brien BJ, Kalloniatis M (2014). "Vinpocetine regulates cation channel permeability of inner retinal neurons in the ischaemic retina". Neurochem. Int. 66C: 1–14. doi:10.1016/j.neuint.2014.01.003. PMID 24412512.
- Herrera-Mundo N, Sitges M (2013). "Vinpocetine and α-tocopherol prevent the increase in DA and oxidative stress induced by 3-NPA in striatum isolated nerve endings". J. Neurochem. 124 (2): 233–40. doi:10.1111/jnc.12082. PMID 23121080.
- Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG (2011). "TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation". Neuron Glia Biol. 7 (2–4): 187–97. doi:10.1017/S1740925X12000129. PMID 22874716.
- Bönöczk P, Panczel G, Nagy Z (2002). "Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study". Eur J Ultrasound. 15 (1–2): 85–91. doi:10.1016/s0929-8266(02)00006-x. PMID 12044859.
- Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J (2000). "Neuroprotective antioxidants from marijuana". Ann. N. Y. Acad. Sci. 899: 274–82. doi:10.1111/j.1749-6632.2000.tb06193.x. PMID 10863546.
- Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality". Ann Intern Med. 142 (1): 37–46. doi:10.7326/0003-4819-142-1-200501040-00110. PMID 15537682.
- Kelton MC, Kahn HJ, Conrath CL, Newhouse PA (2000). "The effects of nicotine on Parkinson's disease". Brain Cogn. 43 (1–3): 274–82. PMID 10857708.
- 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.
- 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.
- Xu K, Xu YH, Chen JF, Schwarzschild MA (2010). "Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson's disease". Neuroscience. 167 (2): 475–81. doi:10.1016/j.neuroscience.2010.02.020. PMC 2849921. PMID 20167258.
- Aoyama K, Matsumura N, Watabe M, Wang F, Kikuchi-Utsumi K, Nakaki T (2011). "Caffeine and uric acid mediate glutathione synthesis for neuroprotection". Neuroscience. 181: 206–15. doi:10.1016/j.neuroscience.2011.02.047. PMID 21371533.
- 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". J. Neurochem. 93 (6): 1542–50. doi:10.1111/j.1471-4159.2005.03146.x. PMID 15935070.
- Gunasekaran R, Narayani RS, Vijayalakshmi K, Alladi PA, Shobha K, Nalini A, Sathyaprabha TN, Raju TR (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 Res. 1255: 170–9. doi:10.1016/j.brainres.2008.11.099. PMID 19109933.
- Sinclair HL, Andrews PJ (2010). "Bench-to-bedside review: Hypothermia in traumatic brain injury". Crit Care. 14 (1): 204. doi:10.1186/cc8220. PMC 2875496. PMID 20236503.
- Leeds PR, Yu F, Wang Z, Chiu C-T, Zhang Y, Leng Y, Linares GR, Chuang D-M (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.
- Bazan NG (2006). "The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling". Cellular and Molecular Neurobiology. 26 (4–6): 901–13. doi:10.1007/s10571-006-9064-6. PMID 16897369.
- 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 (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.
- Serhan CN, Chiang N, Dalli J (2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology. 27 (3): 200–15. doi:10.1016/j.smim.2015.03.004. PMC 4515371. PMID 25857211.
- Dodd S, Maes M, Anderson G, Dean OM, Moylan S, Berk M (2013). "Putative neuroprotective agents in neuropsychiatric disorders". Progress in Neuro-psychopharmacology & Biological Psychiatry. 42: 135–45. doi:10.1016/j.pnpbp.2012.11.007. PMID 23178231. Retrieved 2016-01-03.
- Venkatesan R, Ji E, Kim SY (2015). "Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review". BioMed Research International. 2015: 1–22. doi:10.1155/2015/814068. PMC 4446472. PMID 26075266.
- Jain KK (2011). The Handbook of Neuroprotection. Totowa, NJ: Humana Press. ISBN 978-1-61779-048-5.
- Borsello T (2007). Neuroprotection Methods and Protocols (Methods in Molecular Biology). Totowa, NJ: Humana Press. p. 239. ISBN 978-1-58829-666-5.
- Alzheimer C (2002). Molecular and cellular biology of neuroprotection in the CNS. New York: Kluwer Academic / Plenum Publishers. ISBN 978-0-306-47414-9.