Some other stimulants, in appropriate doses, can however be neuroprotective. Selegiline: It has been shown to slow early progression of. We review the mechanisms by which hypothermia confers neuroprotection as .. Therapeutic hypothermia consists of 3 phases: induction, maintenance, and. Neuroprotective and disease-modifying effects of the ketogenic diet . A third variation on the diet, known as the Radcliffe Infirmary diet, represents a.
Neuroprotection 3 –
Therefore, based on these results, the synergic neuroprotective effect of forskolin, homotaurine, and L-carnosine has been investigated in a rat model of experimental glaucoma [ 61 ]. Such neuroprotective effect is also correlated with the reduction of calpain activity, known to be linked to neurodegenerative events [ 66 , 67 ]. Support of the above comes from a recent clinical study [ 68 ] carried out on glaucomatous patients with IOP compensated by topical drugs, which evaluated the additional neuroprotective effect of the food supplement containing forskolin, homotaurine, carnosine, folic acid, vitamins B1, B2, and B6, and magnesium.
Treatment with the food supplement resulted in a further significant decrease of the IOP most likely due to forskolin and an improvement of PERG amplitude and foveal sensitivity, parameters related to RGC function.
Saffron is derived from the pistils of Crocus sativus , a well-known traditional Chinese medicine [ 69 ], and contains high concentrations of the carotenoids crocin and crocetin. Multiple divalent carbon bonds in saffron compounds confer their powerful radical scavenging and antioxidative properties [ 70 — 72 ].
It is likely because of this antioxidant effect on a clogged trabecular meshwork that high dose oral saffron treatment may further decrease IOP in POAG patients already undergoing different hypotonizing treatments [ 73 ]. More recent studies have highlighted the neuroprotective properties of saffron.
In a rat model of continuous blue light exposure, saffron dietary supplement protects photoreceptors from photooxidative damage, maintaining both morphology and function [ 74 ]. Similar results against light-induced damage were obtained in mice and were attributed to the inhibition of caspase activity [ 75 ]. The main saffron components of interest for their associated biological activity are the carotenoid derivatives crocetin and crocin [ 69 ]. Ocular hypertension, as well as the consequent reduced blood flow into the eye circulation, is the basis for the longstanding ischemic hypothesis of glaucoma [ 77 , 78 ].
Crocin improves both the retinal and the choroidal blood flow in vivo and consequently facilitates retinal function recovery following IOP increase [ 79 ]. Experimental studies have shown that brimonidine has also neuroprotective activity. In a retinal ischemia model, the intraperitoneal administration of brimonidine prevented the accumulation of toxic concentrations of extracellular glutamate and aspartate and preserved the ERG-b wave [ 86 ]. Similarly, systemic treatment with brimonidine prevented the elevation of N-methyl-D-aspartate NMDA receptor expression in rat ischemic retinal injury induced by acute IOP elevation [ 87 ] and limited RGC death in both an isolated rat retina and an in vivo rabbit retinal excitotoxicity model, through the modulation of the NMDA receptor function [ 88 ].
Systemic administration of brimonidine has been shown to protect RGC in a rat model in which chronic ocular hypertension was induced by laser photocoagulation of the trabeculae [ 89 ]. Brimonidine has been shown to upregulate neurotrophic factors expression in the retina, such as fibroblast growth factor 2 FGF2 and BDNF [ 90 , 91 ]. The neuroprotective effects of brimonidine on RGC are also evident after topic ocular administration in adult rats [ 92 ]. Clinical studies have shown that topical brimonidine improved the visual outcome of patients undergoing laser treatment for classic extrafoveal or juxtafoveal choroidal neovascularization treatment [ 93 ] and that brimonidine, but not timolol, topical therapy, improved contrast sensitivity of glaucoma patients after 3 months of treatment [ 94 ].
More recently, a long-term clinical study has indicated that topical brimonidine treatment may indeed protect the RGC of glaucomatous patients. The clinical comparison between brimonidine and timolol in preserving the visual function of NTG patients over a period of 4 years of observation has shown that, despite an identical effect on IOP, after 2 years, those patients treated with brimonidine were less likely to have disease progression than those treated with timolol [ 95 ].
Citicoline is a naturally occurring cell endogenous compound, intermediate in the synthesis of membrane phospholipids such as phosphatidylcholine [ 96 ].
Experimental studies have shown that citicoline may indeed increase the synthesis of phospholipids in the CNS [ 97 ] and indicated a neuromodulator effect and a protective role of this molecule on RGC [ 98 ]. In rodent retinal cultures and animal models, citicoline triggered antiapoptotic effects, increased the retinal level of dopamine one of the most important neurotransmitters involved in retinal and postretinal visual pathways [ 99 ], and prevented the thinning of retinal nerve fiber layer [ ].
However, whether dopamine itself works as a neuroprotectant for RGC is not clear yet, since no direct effects of dopamine on RGC survival have been reported.
Citicoline has been shown to protect the retina in vivo against kainate-induced neurotoxicity [ ] and to rescue rat RGC following partial optic nerve crush [ ].
A beneficial effect of citicoline oral supplement has been demonstrated in patients with nonarteritic ischemic optic neuropathy. At the end of the study, PERG, visual evoked potentials, and visual acuity were improved compared to pretreatment values and to a group of patients with no treatment during the same period [ ]. Other clinical studies reported citicoline neurotrophic effects in POAG management [ — ].
Melatonin is a hormone ubiquitously distributed in living systems, from bacteria to plants and animals. The pineal gland is the main source of melatonin, although other organs and cells such as skin, gastrointestinal tract, platelets, and lymphocytes can also make it [ ].
Melatonin receptors MT1, MT2, and to a lesser extent MT3 are consequently found in many tissues [ ], including the eye, where they are well represented in retinal cells [ ] and the ciliary epithelium [ ].
The lipophilic nature of melatonin allows it to easily cross the hematoencephalic and hematoretinal barriers, thus reaching all tissues and the eye with good efficiency in a short time [ ]. Melatonin can affect tissue metabolism and survival via receptor-independent and receptor-dependent mechanisms. The main receptor-independent activity is due to its strong antioxidant potential.
Melatonin is a potent free radical scavenger and antioxidant, different from the other typical antioxidants. In fact, melatonin and its metabolites are able to neutralize numerous toxic oxygen and nitrogen reactive species ROS and NOS, resp. Therefore, melatonin is a more potent antioxidant than vitamins E and C [ ].
Moreover, the large spectrum antioxidant activity of melatonin is potentiated by its regulatory activity on endogenous antioxidant and prooxidant enzymes, upregulating the former and downregulating the latter [ ]. These activities designate melatonin as a neuroprotective agent in several neurodegenerative diseases, in which oxidative damage to neurons is a major player [ ].
In the eye, melatonin has been shown to protect human retinal pigment epithelial cells against oxidative stress [ ] and to slow down photoreceptor degeneration in a mouse model of retinitis pigmentosa [ ]. Moreover, the suppression of melatonin subtype receptor MT1 has been shown to decrease the viability of photoreceptors and RGCs [ , ]. Glutamate accumulation in extracellular spaces can be potentially neurotoxic to the retina [ ], and the impairment of glutamate transporter expression precedes the depression of glutamine synthase activity during ocular pressure loading [ ].
In the hamster retina, it has been shown that melatonin may increase glutamate uptake and glutamine synthase activity, thus decreasing glutamate neurotoxicity [ ]. Melatonin and its analogs have shown hypotonizing effects in both experimental animal models and glaucomatous patients [ — ]. Significant reductions of retinal melatonin levels were found in the rat model of glaucoma induced by chronic ocular hypertension [ ]. The localization of melatonin receptors in the iris and ciliary processes strongly suggests that they are indeed involved in IOP regulation [ , ], most likely through a mechanism that involves the putative MT3 receptors and a local increase in cAMP [ ], similar to what has been described before for forskolin Figure 3 a.
Correspondingly, preliminary clinical observations indicate a cooperative effect on IOP reduction by melatonin and forskolin Pescosolido, personal communication. Hypoxia has also been involved in the development of glaucoma [ — ]. Melatonin has shown neuroprotective effects against hypoxia-induced retinal ganglion cell death in neonatal rats [ ].
Impairment of ocular blood flow is also a relevant player in the etiopathogenesis and progression of the glaucomatous optic neuropathy [ ]. IOP or blood pressure circadian fluctuations cause an unstable oxygen supply, triggering further damage to RGCs [ ].
Melatonin might contribute to the attenuation of these events, both on the IOP and on the blood flow control sides, since it is known to have vasoactive properties and shown to modulate arterial vasoconstriction [ ]. Recognizing its beneficial antioxidant and ocular hypotensive properties, several melatonin related compounds, such as the synthetic analogs and the specific agonists of melatonin receptors, are under investigation [ ].
Among the melatonin analogs, agomelatine is currently attracting interest for its pharmacological activities [ , , , — ]. Agomelatine is a drug used in the treatment of major depressive disorders. In a recent clinical study, the hypotensive activity of oral agomelatine in eyes of POAG patients was revealed: Agomelatine has also shown neuroprotective effects: In vivo treatment with agomelatine reduces the chronic cerebral hypoperfusion responsible for vascular dementia and limits cholinergic dysfunction, oxidative stress, and tissue damage in mice [ ].
The neuroprotective effects of agomelatine and melatonin against NMDA-receptor-mediated white matter lesions have been shown in a newborn mouse experimental model. Mice that received intraperitoneal agomelatine or melatonin had significant reductions in size of white matter cysts induced by the glutamatergic analog, when compared with controls [ ]. Ginkgo biloba is a native tree of China with various uses in traditional medicine and also as a source of food [ ].
The leaf extract from Ginkgo biloba GBE is rich in biologically active ingredients mainly flavonoids and terpenoids , which can scavenge free radicals and protect cells from lipid peroxidation [ — ]. More interestingly, the polyphenolic flavonoids that are richly present in GBE can act as antioxidants at the mitochondrial level where other antioxidants cannot work , stabilizing mitochondrial membranes and improving their energetic balance specifically in neuronal cells [ , ].
This is an important contribution for glaucoma treatment, since mitochondrial dysfunction has been strongly implicated in POAG pathogenesis [ ]. In several experimental studies, GBE has been shown to exert antioxidant and neuroprotective properties [ — ].
Elevated levels of nitric oxide contribute significantly to the pathogenesis of ocular diseases [ ]. Nitric oxide reacts with superoxides to form peroxynitrites [ ], which cause nitrosylation of cellular proteins, DNA, and lipids, ultimately leading to RGC death [ ]. It was demonstrated in vitro that GBE can scavenge nitric oxide [ ] and possibly inhibit its production [ ]. The protective activity of GBE on isolated rat retinas was evaluated on rats orally treated versus untreated controls with the extract for 10 days.
Upon a challenge of the isolated retinas with an oxidant perfusion, GBE contrasted the decrease of ERG-b wave amplitude due to the oxidative damage [ ]. The unstable oxygen supply to the retina and the optic nerve caused by high IOP, blood pressure fluctuations, or disturbed autoregulation also leads to increased oxidative stress, a main contributor to glaucomatous damage [ ].
Beside its antioxidant properties, GBE also shows hemorheological and vasoactive effects, promoting erythrocytes deformability, decreasing fibrinogen levels, and improving blood viscosity and viscoelasticity [ ], and increases microcirculation by improving the endothelium-dependent vasodilation [ ]. Consistently, clinical observation has shown that GBE was able to significantly increase diastolic and systolic velocity in the ophthalmic artery OA of healthy volunteers [ ].
Another clinical study evaluated the effects of GBE in NTG patients, in which vascular dysregulation appears to play a critical role. In another controlled clinical study on 52 POAG patients, those treated with GBE showed, after 3 months of treatment, a relevant decrease of endothelin-1 ET1, responsible for peripheral vasoconstriction , resulting in increased flow-dependent vasodilation.
This was paralleled by a decrease of malondialdehyde-modified low-density lipoproteins and plasma malondialdehyde levels, indicating the activation of an antioxidant response and the attenuation of oxidative stress [ ]. Apoptotic cell death is a hallmark of POAG damage and has been shown at the level of the trabecular meshwork [ ] and the RGC layer [ ].
GBE also shows antiapoptotic properties. Pheochromocytoma cells PC12 treated with GBE were protected from mitochondrial damage induced by serum deprivation or by staurosporine through mechanisms that result in attenuated release of cytochrome-C and less DNA fragmentation, while DNA microarray assay results indicate that transcription of multiple apoptosis-related genes is either up- or downregulated in cells treated with GBE [ ].
Moreover, GBE effects on mitochondria-dependent caspase pathway in cardiomyocytes exposed for 24 hours to hypoxia and four hours to reoxygenation resulted in inhibition of cytochrome-C release from mitochondria, thus decreasing caspase-3 activity and the resulting apoptotic cell death [ ].
Finally, in an experimental in vivo study, it was demonstrated that GBE inhibited the apoptosis of RGC in guinea pigs after optic nerve transection, thus protecting their morphology and function [ ]. Another even more specific agent targeting mitochondria for neuroprotection is the coenzyme Q10 CoQ10 , which is an essential membrane cofactor, with a strong antioxidant activity, in the mitochondrial respiratory chain [ , ]. It also appears to be able to modulate gene expression with anti-inflammatory effects [ ].
In fact, in neurodegenerative diseases, external oxidative stress induces mitochondrial dysfunction, which in turn leads to the increase of ROS generation, and finally leads to apoptotic cell death of the neuronal cells [ ].
CoQ10 has been shown to inhibit ROS generation, to maintain mitochondrial membrane potential during oxidative stress, and to reduce the amount of mitochondrial ROS generation in neuronal cell cultures [ ]. Furthermore, the inhibition of oxidative stress by CoQ10 increases the mitochondrial mass and improves the bioenergetic function in primary optic nerve head rat astrocyte cultures [ ].
High levels of glutamate have been found in the retina of animal models of glaucoma [ , ]. Accordingly, it has been reported that CoQ10 protects retinal cells in vitro against oxidative stress induced by hydrogen peroxide and protects them in vivo after intravitreal injection of N-methyl-D-aspartate [ ].
In a similar experiment, it was demonstrated that CoQ10 results in RGC protection after artificial elevation of extracellular glutamate [ ]. Glaucoma is widely known to be associated with increased RGC apoptosis [ ]. Caspase-7 plays a critical role in this process [ ] since RGCs of mice knocked out for caspase-7 have been shown to be protected from apoptotic death [ ].
More recent data also suggest an important role for Fas receptors and caspasemediated apoptosis in the pathophysiology of glaucomatous neurodegeneration [ ]. Along this line, the antiapoptotic activity of CoQ10 has been evaluated in a rat model of cultured RGCs exposed to external damage and in a mouse model of kainic acid-induced retinal damage.
Patients treated with such association showed PERG improvement with consequent enhancement of the visual cortical responses [ ].
Timolol is a nonselective beta-adrenergic receptor antagonist and is one of the main molecules indicated for glaucoma treatment. Unfortunately, in some cases, adverse cardiovascular effects can occur, and CoQ10 has been shown to be effective in reducing such systemic side effects induced by timolol [ , ].
Polyphenols are secondary plant metabolites generally synthesized from phenylalanine and used by plants in the defense against ultraviolet radiation or aggression by pathogens [ ]. In the last decades, together with the realization that many pathologies, and aging itself, are caused by an excess of oxidative damage, there has been much attention to the health benefits of plant polyphenols mainly those belonging to the class of flavonoids , due to their strong antioxidant properties [ ].
Catechins are flavanols, a subclass of flavonoids. They are the main components of green tea extract, among which epigallocatechin gallate EGCG, also known as epigallocatechingallate is the most abundant. Catechins may act as radical scavengers, iron chelators, and modulators of prosurvival genes expression and the PKC signaling pathway [ , ]. Along a similar line, it was shown that oral administration of EGCG protects RGCs from degeneration in a mouse model of chronic glaucoma obtained after microbeads injection in the anterior chamber [ ] and in the optic nerve crush rat model [ ].
Intravitreal injection of oxidants such as sodium nitroprusside which generates NO spontaneously triggers significant photoreceptor apoptosis with the rest of the retina relatively unaffected [ , ]. When EGCG is injected into the rat eye together with sodium nitroprusside, its detrimental influence on retinal photoreceptors was attenuated [ ].
EGCG is nongenotoxic, even when administered to animals at doses that are significantly higher than those intended for humans [ ]. Clinical efficacy of a short-term oral supplementation of EGCG has been studied by PERG analysis addressing the electrical activity of RGC , showing that the treatment might favorably influence the inner retinal function in human eyes of glaucomatous patients with early to moderately advanced damage [ ].
This results in loss of electrolyte gradients, with cell swelling and necrosis. The damage during this period occurs prior to hypothermia therapy and will not be affected by treatment. After reperfusion of the brain, there is further evolution of cell death. During this phase of secondary energy failure the decline in phosphocreatine and ATP is not accompanied by brain acidosis, but it results in apoptosis, or programmed cell death.
Apoptosis extends over several days, and the degree of energy failure and apoptosis is proportional to the severity of adverse neurodevelopmental outcomes seen later at one and four years of age. It is this phase of HIE that hypothermia attempts to ameliorate. Fortunately, there is a brief recovery latency period between the two phases of injury that provides a therapeutic window for treatment. After reperfusion but before secondary energy failure there is a brief period following resuscitation when brain oxidative metabolism and cellular pH recover before the second phase of injury.
Initial studies performed in animal models showed that hypothermia during this period was neuroprotective. It was concluded that cooling should be initiated as early as possible after the initial injury preferably within 2, but no later than 6 hours and should continue for 48 to 72 hours. The initial hypothermia trials with two separate devices were run concurrently Fig. Thus, inclusion criteria for use of both devices is very similar with the exception of the aEEG requirement.
Major clinical trials have examined the outcomes in both selective head cooling and whole body cooling. A meta-analysis of the three major trials examined the primary outcomes of death in infants and major neurodevelopmental disability after 18 months in infants. The inclusion criteria for both devices are listed in Table 1. If the child meets the initial criteria items 1, 2, and 3 on Table 1 , the child is placed on an aEEG. Figure 5 shows an example of a moderately abnormal tracing bottom row as compared to the normal tracing on the top row.
Our institution continues the aEEG throughout the 72 hour cooling process. Examples of aEEG tracings. Normal top tracing shows normal variability and sleep-wake cycle compared to moderately abnormal tracing on bottom.
Many of these children have systemic collapse associated with their HIE and close monitoring of injury to the heart, lungs, kidneys, and liver is critical. Ongoing laboratory measurements include blood gases, liver function tests, CPK, and electrolytes, as well as close monitoring of input and output.
Good cardiac output and blood pressure are maintained to optimize brain perfusion. Acidosis and electrolyte imbalances are corrected, and normal glucose levels are preserved.
Many of these infants require ventilator support as well as pressor support in order to achieve good oxygenation and perfusion. Several of our infants have required advanced respiratory support, including inhaled nitric oxide and extracorporeal membrane oxygenation ECMO for support of their pulmonary and cardiovascular systems.
Nursing care for hypothermia therapy includes close monitoring of neurologic status, and observation for clinical or sub-clinical seizures on aEEG. The nursing staff observes the infants for pain as well as any complications due to skin exposure to the cap or blanket.
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