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.[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 . 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

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 signaling.

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.