Neuroprotection

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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, and spinal cord injury. 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 include increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation.[2][3][4] 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.[5] 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.[5][6] As Ca2+ accumulates in the neuron, the buffering levels of mitochondrial Ca2+ sequestration are exceeded, which has major consequences for the neuron.[5] 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.[7][8][9] Ca2+ is also thought to trigger neuroinflammation, a key component in all CNS disorders[5]

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.[10]
  • 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[6]
  • Progesterone: Administration of progesterone is well known to aid in the prevention of secondary injuries in patients with traumatic brain injury and stroke[9]
  • 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[10]

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.[4][5] 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][3][4][11] If one of these events is triggered, further neurodegradation is caused as each of these events causes neuron cell apoptosis.[3][4][11] By decreasing oxidative stress through neuroprotective treatments, further neurodegradation can be inhibited.

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:

  • Deprenyl: This has been shown to slow early progression of symptoms and delayed the emergence of disability by an average of nine months.[3]
  • 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.[12]
  • 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[13]
  • 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.[14][15]
  • 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.[16][17]
  • 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. Vitamin E ineffective for neuroprotection in Parkinson's disease.[3][4]

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.[18]
  • 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[19]
  • Anti protein aggregation agents: Protein aggregation is a known source of neuron cell death. Different treatments are being looked at for potentially eliminating this as a source of neurodegeneration. These include sodium 4-phenylbutyrate, trehalose, and polyQ-binding peptide.[20]
  • 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.[21]

References

  1. ↑ 1.0 1.1 Casson, R.J.; Chidlow G., Ebneter A., Wood J.P.M., Crowston J.G., Goldberg I. (2012). "Translational neuroprotection research in glaucoma: A review of definitions and principles". Clin Exp Ophthalmol 40 (4): 350–7. doi:10.1111/j.1442-9071.2011.02563.x. PMID 22697056. 
  2. ↑ 2.0 2.1 2.2 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. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Andersen JK (July 2004). "Oxidative stress in neurodegeneration: cause or consequence?". Nat. Med. 10 Suppl (7): S18–25. doi:10.1038/nrn1434. PMID 15298006. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 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. 
  6. ↑ 6.0 6.1 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. 
  7. ↑ Sattler R, Tymianski M (2000). "Molecular mechanisms of calcium-dependent excitotoxicity". J. Mol. Med. 78 (1): 3–13. doi:10.1007/s001090000077. PMID 10759025. 
  8. ↑ 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. 
  9. ↑ 9.0 9.1 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. 
  10. ↑ 10.0 10.1 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". J. Neurosci. 32 (14): 4887–900. doi:10.1523/JNEUROSCI.5828-11.2012. PMID 22492045. 
  11. ↑ 11.0 11.1 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. 
  12. ↑ 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. PMID 9106616. 
  13. ↑ 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. 
  14. ↑ Tikka TM, Koistinaho JE (June 2001). "Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia". J. Immunol. 166 (12): 7527–33. PMID 11390507. 
  15. ↑ 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. 
  16. ↑ 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. 
  17. ↑ 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. 
  18. ↑ 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. 
  19. ↑ 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. 
  20. ↑ Ge P, Luo Y, Wang H, Ling F (December 2009). "Anti-protein aggregation is a potential target for preventing delayed neuronal death after transient ischemia". Med. Hypotheses 73 (6): 994–5. doi:10.1016/j.mehy.2008.10.041. PMID 19560879. 
  21. ↑ 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. 

Further reading

  • Kewal K. Jain (2011). The Handbook of Neuroprotection. Totowa, NJ: Humana Press. ISBN 1-61779-048-6. 
  • Tiziana Borsello (2007). Neuroprotection Methods and Protocols (Methods in Molecular Biology). Totowa, NJ: Humana Press. p. 239. ISBN 1-58829-666-0. 
  • Christian Alzheimer (2002). Molecular and cellular biology of neuroprotection in the CNS. New York: Kluwer Academic / Plenum Publishers. ISBN 0-306-47414-X. 
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