Fetal or neonatal brain injury can result in lifelong neurologic disability. The most significant risk factor for perinatal brain injury is prematurity; however, in absolute numbers, full-term infants represent the majority of affected children. Research on strategies to prevent or mitigate the impact of perinatal brain injury ("perinatal neuroprotection") has established the mitigating roles of magnesium sulfate administration for preterm infants and therapeutic hypothermia for term infants with suspected perinatal brain injury. Banked umbilical cord blood, erythropoietin, and a number of other agents that may improve neuronal repair show promise for improving outcomes following perinatal brain injury in animal models. Other preventative strategies include delayed umbilical cord clamping in preterm infants and progesterone in women with prior preterm birth or short cervix and avoidance of infections. Despite these advances, we have not successfully decreased the rate of preterm birth, nor are we able to predict term infants at risk of hypoxic brain injury in order to intervene prior to the hypoxic event. Further, we lack the ability to modulate the sequelae of neuronal cell insults or the ability to repair brain injury after it has been sustained. As a consequence, despite exciting advances in the field of perinatal neuroprotection, perinatal brain injury still impacts thousands of newborns each year with significant long-term morbidity and mortality.

Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents' efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.

Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model.

Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester (CAPE), is one of the most extensively investigated active components of propolis. Several studies have indicated that CAPE has a broad spectrum of pharmacological activities as anti-oxidant, anti-inflammatory, anti-viral, anti-fungal, anti-proliferative, and anti-neoplastic properties. This review largely describes CAPE neuroprotective effects in many different conditions and summarizes its molecular mechanisms of action. CAPE was found to have a neuroprotective effect on different neurodegenerative disorders. At the basis of these effects, CAPE has the ability to protect neurons from several underlying causes of various human neurologic diseases, such as oxidative stress, apoptosis dysregulation, and brain inflammation. CAPE can also protect the nervous system from some diseases which negatively affect it, such as diabetes, septic shock, and hepatic encephalopathy, while numerous studies have demonstrated the neuroprotective effects of CAPE against adverse reactions induced by different neurotoxic substances. The potential role of CAPE in protecting the central nervous system (CNS) from secondary injury following various CNS ischemic conditions and CAPE anti-cancer activity in CNS is also reviewed. The structure-activity relationship of CAPE synthetic derivatives is discussed as well.

Over the last two decades there has been an exponential rise in the number of patients receiving deep brain stimulation (DBS) to manage debilitating neurological symptoms in conditions such as Parkinson's disease, essential tremor, and dystonia. Novel applications of DBS continue to emerge including treatment of various psychiatric conditions (e.g. obsessive-compulsive disorder, major depression) and cognitive disorders such as Alzheimer's disease. Despite widening therapeutic applications, our understanding of the mechanisms underlying DBS remains limited. In addition to modulation of local and network-wide neuronal activity, growing evidence suggests that DBS may also have important neuroprotective effects in the brain by limiting synaptic dysfunction and neuronal loss in neurodegenerative disorders. In this review, we consider evidence from preclinical and clinical studies of DBS in Parkinson's disease, Alzheimer's disease, and epilepsy that suggest chronic stimulation has the potential to mitigate neuronal loss and disease progression.

Niaspan, an extended-release formulation of Niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. In this study, we tested whether Niaspan administered acutely after stroke is neuroprotective.

Most homeoprotein transcription factors have a highly conserved internalization domain used in intercellular transfer. Internalization of homeoproteins ENGRAILED1 or ENGRAILED2 promotes the survival of adult dopaminergic cells, whereas that of OTX2 protects adult retinal ganglion cells. Here we characterize the in vitro neuroprotective activity of several homeoproteins in response to H2O2 Protection is observed with ENGRAILED1, ENGRAILED2, OTX2, GBX2, and LHX9 on midbrain and striatal embryonic neurons, whereas cell-permeable c-MYC shows no protective effects. Therefore, five homeoproteins belonging to three different classes (ANTENNAPEDIA, PAIRED, and LIM) share the ability to protect embryonic neurons from midbrain and striatum. Because midbrain and striatal neurons do not express the same repertoire of the four proteins, a lack of neuronal specificity together with a general protective activity can be proposed. Interestingly, hEN1 and GBX2 provided protection to primary midbrain astrocytes but not to non-neural cells, including mouse embryo fibroblasts, macrophages or HeLa cells. For the four proteins, protection against cell death correlated with a reduction in the number of H2O2-induced DNA break foci in midbrain and striatal neurons. In conclusion, within the limit of the number of cell types and homeoproteins tested, homeoprotein protection against oxidative stress-induced DNA breaks and death is specific to neurons and astrocytes but shows no homeoprotein or neuronal type specificity.

Reactive oxygen species (ROS) play an important role in aging and age-related diseases such as Parkinson's disease and Alzheimer's disease. Much of the ROS production under conditions of toxic stress is from mitochondria, and multiple antioxidants prevent ROS accumulation. The aim of this study is to examine the specificity of the interaction between the antioxidants and ROS production in stressed cells.

We previously demonstrated that the neuropeptide cocaine- and amphetamine-regulated transcript (CART) is protective against focal cerebral ischemia in vivo and against neuronal cell death in culture induced by oxygen-glucose deprivation (OGD). The mechanism of neuroprotection by CART is unknown, in part due to lack of knowledge regarding its putative receptor. Using a yeast two-hybrid system with CART's carboxy-terminal to screen a mouse brain cDNA library, we uncovered a potential direct interaction between CART and subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB). We confirmed CART/SDHB binding using in vitro pull-down assay, and tested the effects of CART peptide on SDH activity, Complex II (CII) activity and ATP production in primary cultured cortical neurons under basal conditions and after OGD. At concentrations between 0.2 and 4 nM, CART significantly increased SDH function, CII activity and ATP generation in purified mitochondria and intact neurons under baseline conditions. Furthermore, pretreatment with CART enhanced mitochondrial mechanisms of neuronal survival and prevented the decline in SDH and CII activities and ATP production after OGD. The findings suggest that CART's neuroprotective mechanism of action may be linked to preservation of mitochondrial function and prevention of energy failure after ischemia-reperfusion injury.

Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.

In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.

Retinal ganglion cell (RGC) loss after optic nerve damage is a hallmark of certain human ophthalmic diseases including ischemic optic neuropathy (ION) and glaucoma. In a rat model of optic nerve transection, in which 80% of RGCs are eliminated within 14 days, caspase-2 was found to be expressed and cleaved (activated) predominantly in RGC. Inhibition of caspase-2 expression by a chemically modified synthetic short interfering ribonucleic acid (siRNA) delivered by intravitreal administration significantly enhanced RGC survival over a period of at least 30 days. This exogenously delivered siRNA could be found in RGC and other types of retinal cells, persisted inside the retina for at least 1 month and mediated sequence-specific RNA interference without inducing an interferon response. Our results indicate that RGC apoptosis induced by optic nerve injury involves activation of caspase-2, and that synthetic siRNAs designed to inhibit expression of caspase-2 represent potential neuroprotective agents for intervention in human diseases involving RGC loss.

Glaucoma is one of the most frequent causes of visual impairment worldwide, and involves selective damage to retinal ganglion cells (RGCs) and their axons. We analyzed the effect of enriched environment (EE) housing on the optic nerve, and retinal alterations in an induced model of ocular hypertension. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate (CS) into the eye anterior chamber for 10 weeks and housed in standard environment or EE. EE housing prevented the effect of experimental glaucoma on visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament-immunoreactivity, axon number, microglial/macrophage reactivity (ionized calcium binding adaptor molecule 1-immunoreactivity), and astrocytosis (glial fibrillary acidic protein-immunostaining), as well as oligodendrocytes alterations (luxol fast blue staining, and myelin basic protein-immunoreactivity) in the proximal portion of the optic nerve. Moreover EE prevented the increase in ionized calcium binding adaptor molecule-1 levels, and RGC loss (Brn3a-immunoreactivity) in the retina from hypertensive eyes. EE increased retinal brain-derived neurotrophic factor levels. When EE housing started after 6 weeks of ocular hypertension, a preservation of visual evoked potentials amplitude, axon, and Brn3a(+) RGC number was observed. Taken together, these results suggest that EE preserved visual functions, reduced optic nerve axoglial alterations, and protected RGCs against glaucomatous damage.

This review is centered on the pivotal role of surgical interventions within the comprehensive management of traumatic brain injury (TBI). Surgical strategies are indispensable components of TBI care, encompassing primary injury management and the alleviation of secondary injury processes, including the handling of intracranial hemorrhages (ICHs), contusions, and mass lesions.

G-protein-coupled estrogen receptor-30 (GPR30), also known as G-protein estrogen receptor-1 (GPER1), is a putative extranuclear estrogen receptor whose precise functions in the brain are poorly understood. Studies using exogenous administration of the GPR30 agonist, G1 suggests that GPR30 may have a neuroprotective role in cerebral ischemia. However, the physiological role of GPR30 in mediating estrogen (E2)-induced neuroprotection in cerebral ischemia remains unclear. Also unclear is whether GPR30 has a role in mediating rapid signaling by E2 after cerebral ischemia, which is thought to underlie its neuroprotective actions. To address these deficits in our knowledge, the current study examined the effect of antisense oligonucleotide (AS) knockdown of GPR30 in the hippocampal CA1 region upon E2-BSA-induced neuroprotection and rapid kinase signaling in a rat model of global cerebral ischemia (GCI). Immunohistochemistry demonstrated that GPR30 is strongly expressed in the hippocampal CA1 region and dentate gyrus, with less expression in the CA3 region. E2-BSA exerted robust neuroprotection of hippocampal CA1 neurons against GCI, an effect abrogated by AS knockdown of GPR30. Missense control oligonucleotides had no effect upon E2-BSA-induced neuroprotection, indicating specificity of the effect. The GPR30 agonist, G1 also exerted significant neuroprotection against GCI. E2-BSA and G1 also rapidly enhanced activation of the prosurvival kinases, Akt and ERK, while decreasing proapototic JNK activation. Importantly, AS knockdown of GPR30 markedly attenuated these rapid kinase signaling effects of E2-BSA. As a whole, the studies provide evidence of an important role of GPR30 in mediating the rapid signaling and neuroprotective actions of E2 in the hippocampus.

Aberrant calcium signaling is a common feature of ischemia and multiple neurodegenerative diseases. While activation of calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a key event in calcium signaling, its role in excitotoxicity is controversial. Our findings demonstrate neuroprotection in neuronal cultures treated with the small molecule (KN-93) and peptide (tat-AIP and tat-CN21) inhibitors of CaMKII immediately prior to excitotoxic glutamate/glycine insult. Unlike KN-93 which blocks CaMKII activation, but not constitutively active forms of CaMKII, tat-CN21 and tat-AIP significantly reduced excitotoxicity in cultured neurons when applied post-insult. We observed that the neuroprotective effects of tat-CN21 are greatest when applied before the toxic glutamate challenge and diminish with time, with the neuroprotection associated with CaMKII inhibition diminishing back to control 3h post glutamate insult. Mechanistically, tat-CN21 inhibition of CaMKII resulted in an increase in CaMKII activity and the percentage of soluble αCaMKII observed in neuronal lysates 24h following glutamate stimulation. To address the impact of prolonged CaMKII inhibition prior to excitotoxic insult, neuronal cultures were treated with CaMKII inhibitors overnight and then subjected to a sub-maximal excitotoxic insult. In this model, CaMKII inhibition prior to insult exacerbated neuronal death, suggesting that a loss of CaMKII enhances neuronal vulnerability to glutamate. Although changes in αCaMKII or NR2B protein levels are not responsible for this enhanced glutamate vulnerability, this process is blocked by the protein translation inhibitor cycloheximide. In total, the neuroprotection afforded by CaMKII inhibition can be seen as neuroprotective immediately surrounding the excitotoxic insult, whereas sustained CaMKII inhibition produced by excitotoxicity leads to neuronal death by enhancing neuronal vulnerability to glutamate.

Importance: Hypoxic-ischemic encephalopathy (HIE) is a significant cause of morbidity and mortality in neonates. The incidence of HIE is 1-8 per 1,000 live births in developed countries. Whole-body hypothermia reduces the risk of disability or death, but 7 infants needed to be treated to prevent death or major neurodevelopmental disability. Inhalational gases may be promising synergistic agents due to their rapid onset and easy titratability. Objective: To review current data on different inhaled gases with neuroprotective properties that may serve as adjunct therapies to hypothermia. Evidence review: Literature review was performed using the PubMed database, google scholar, and ClinicalTrials.Gov. Results focused on articles published from January 1, 2005, through December 31, 2017. Articles published earlier than 2005 were included when appropriate for historical perspective. Our review emphasized preclinical and clinical studies relevant to the use of inhaled agents for neuroprotection. Findings: Based on the relevance to our topic, 111 articles were selected pertaining to the incidence of HIE, pathophysiology of HIE, therapeutic hypothermia, and emerging therapies for hypoxic-ischemic encephalopathy in preclinical and clinical settings. Supplemental tables summarizes highly relevant 49 publications that were included in this review. The selected publications emphasize the emergence of promising inhaled gases that may improve neurologic survival and alleviate neurodevelopmental disability when combined with therapeutic hypothermia in the future. Conclusions: Many inhaled agents have neuroprotective properties and could serve as an adjunct therapy to whole-body hypothermia. Inhaled agents are ideal due to their easy administration, titrability, and rapid onset and offset.

Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols.

Blindness in glaucoma is the result of death of Retinal Ganglion Cells (RGCs) and their axons. RGC death is generally preceded by a stage of reversible dysfunction and structural remodeling. Current treatments aimed at reducing intraocular pressure (IOP) are ineffective or incompletely effective in management of the disease. IOP-independent neuroprotection or neuroprotection as adjuvant to IOP lowering in glaucoma remains a challenge as effective agents without side effects have not been identified yet. We show in DBA/2J mice with spontaneous IOP elevation and glaucoma that the lifespan of functional RGCs can be extended by preconditioning RGCs with retrobulbar lidocaine in one eye at four months of age that temporary blocks RGC axonal transport. The contralateral, PBS-injected eye served as control. Lidocaine-induced impairment of axonal transport to superior colliculi was assessed by intravitreal injection of cholera toxin B. Long-term (nine months) effect of lidocaine were assessed on RGC electrical responsiveness (PERG), IOP, expression of relevant protein (BDNF, TrkB, PSD95, GFAP, Synaptophysin, and GAPDH) and RGC density. While lidocaine treatment did not alter the age-related increase of IOP, TrkB expression was elevated, GFAP expression was decreased, RGC survival was improved by 35%, and PERG function was preserved. Results suggest that the lifespan of functional RGCs in mouse glaucoma can be extended by preconditioning RGCs in early stages of the disease using a minimally invasive treatment with retrobulbar lidocaine, a common ophthalmologic procedure. Lidocaine is inexpensive, safe and is approved by Food and Drug Administration (FDA) to be administered intravenously.

Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) is a post-translational protein modification that modulates almost all major cellular processes, and has been implicated in many human diseases. A growing body of evidence from in vitro and in vivo studies demonstrates that increasing global levels of SUMO conjugated proteins (global SUMOylation) protects cells against ischaemia-induced damage, while suppressing global SUMOylation promotes cell injury after ischaemia. Indeed, SUMOylation has emerged as a potential therapeutic target for neuroprotection in brain ischaemia, including global brain ischaemia and focal brain ischaemia (ischaemic stroke). Here, we summarise findings on the role of SUMOylation in human diseases, brain ischaemia in particular, and review recent developments in drug discovery targeting SUMOylation with a major focus on its neuroprotective applications.