Neuroprotection

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.^[7][8] As Ca²⁺ accumulates in the neuron, the buffering levels of mitochondrial Ca²⁺ sequestration are exceeded, which has major consequences for the neuron.^[7] 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.^[9][10][11] Ca²⁺ is also thought to trigger neuroinflammation, a key component in all CNS disorders.^[7]

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.^[6][7] 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.^{[3][5][6][15]} If one of these events is triggered, further neurodegradation is caused as each of these events causes neuron cell apoptosis.^[5][6][15] By decreasing oxidative stress through neuroprotective treatments, further neurodegradation can be inhibited.

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.^[5]
• Nicotine: It has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.^[35][36][37]
• Caffeine: It is protective against Parkinson's disease.^[36][38] Caffeine induces neuronal glutathione synthesis by promoting cysteine uptake, leading to neuroprotection.^[39]

Neuroprotectants (cerebroprotectants) for acute ischemic stroke

This section does not cite any sources. (May 2024)

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, and the approval of edaravone in Japan.

Exercise

Exercise has been put forward as helpful for neuroprotection.^[40][41][42]

Further 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.^[43]
• 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^[44]
• 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.^[45]
• 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.^[46]
• 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.^[47][48] 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.^[49]