In global burden of disease, while cerebrovascular disease

In medical science, brain is among the most dominated complex structure in the humans. It is made up of neurons and neuroglia, the neurons being responsible for sending and receiving nerve impulses or signals. It is assumed that neuroglial activation is largely determined by neuronal signals.( Halliwell, 1992),(Kumar and Khanum, 2012). It is known that brain pathology in the form of cerebrovascular and neurological disease is a leading cause of death all over the world, with an incidence of about 2/1000 and an 8% total death rate in 1995 (Kolominsky et al., 1998).  A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. There are more than 600 neurologic diseases – epilepsy, dementia, parkinson’s. According to Global Burden of Disease (GBD) study, a collaborative endeavour of the World Health Organization (WHO), by 2030 neurological disorders among human community becomes one of the leading causes of death especially in developing and under developing countries (WHO 2006). Developing countries, including India are passing through a phase of epidemiological transition with increasing burden of non-communicable diseases (NCD) consequent to transformation of scenario with improvement of health care services in preventive and promotive domains. Among the NCDs, neurological disorders form a significant proportion of global burden of disease (M Gourie-Devi). The GBD presented the data and estimated the neurological disorders for 2005, 2015 And 2030. Neurological disorders included in the neuropsychiatric category contribute to 2% of the global burden of disease, while cerebrovascular disease and some of the neuroinfections (poliomyelitis, tetanus, meningitis and Japanese encephalitis) contribute to 4.3% of the global burden of disease.Neurological disorders are an important cause of mortality and constitute 12% of total deaths globally by 2030. The DALY’s (Disability Affected Life Years) with neurological disorders for 2005, 2015, 2030 are presented in the Table 1.1 (WHO, 2004). Neurological disorders contribute to 92 million DALY’s in 2005 projected to increase to 103 million in 2030 (approximately a 12% increase) and death attributable to neurological disorders are mentioned in Fig. 1.1.The impact of neurological disorders also depends on the total income category of the person which is shown in Fig. 1.2 Thus, there is seriously a need of protective agents to treat the several neurological disorders and such agents are called as neuroprotective agents or neuroprotectants. Neuroprotection is defined as the ability for a therapy to prevent neuronal cell death by intervening in and inhibiting the pathogenic cascade that results in cell dysfunction and eventual death (Anthony et al., 2009).1.2 Pathogenesis of neuronal damage and cell death Two important processes that lead to irreversible neuronal damage are outlined below.-1.2.1 Rapid necrosis (chaotic cell death)Interruption of blood/oxygen supply to the brain results in dysfunction of ATP dependent ion channels, leading to cellular depolarization and the release of extracellular excitatory neurotransmitters like glutamate. Glutamate activates the N-methyl-D-aspartate (NMDA) receptor subtype of glutamateric receptors. Activation of NMDA receptors increases intracellular calcium and sodium, contributing further to depolarization and neuronal activation. Excess calcium promotes activation of pathways which upset ionic homeostasis, nitric oxide signaling, cytoskeleton function, free radical generation, and protease and lipid activation, ultimately leading to membrane degeneration and excitotoxic cell death (Sanders  et al., 2005)1.2.2 Delayed apoptosis (programmed cellular death)Necrosis and apoptosis are accompanied by an array of other processes which lead to Neurodegeneration (Polster et al., 2004). These include-1.2.2.1 An immunologic (inflammatory) responseRelease of cytokines, such as tumor necrosis factor and interleukins, is mediated by oxidative stress. The significance of the immunologic response is not entirely clear, because it exacerbates oxidative stress on one hand and promotes the removal of dead neurons and neurogenesis on the other (Coimba et al., 1996).1.2.2.2 Oxidative stressOxidative stress is also a feature of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. The brain has a high rate of oxygen consumption, making it susceptible to oxidative stress secondary to the formation of excessive free radicals, which lead to direct tissue damage and stimulate inflammatory and pro-apoptotic cascades (Wang etal, 2006).1.2.2.3 Massive extracellular catecholamine releaseCentral norepinephrine release during brain ischemia increases neuronal metabolism (increases cerebral metabolic rate for oxygen, leads to the formation of free radicals from auto-oxidation of neurotransmitters, such as norepinephrine and dopamine, and exacerbates damage caused by glutamate during ischemia (Ellen et al., 2006).1.3 Features of an ideal neuroprotectantIf an ideal neuroprotectant drug were to be developed, one needs first to consider a simple list of what desirable features of the ideal neuroprotectant drug might be. These must include-(i) Effectiveness pre-ischemia (Gabryel et al., 2012) and posthoc, thus enlarging the window of opportunity for neuroprotective intervention.(ii) A simple route of administration; ideally- orally.(iii) Rapid onset of action(iv) Must possess restorative property.(v) A high tolerability and a low side-effect profile.1.4 Pharmacological strategies and agents for neuroprotection1.4.1 Free radical scavengersFree radicals, especially superoxide (O(2)*-), and non-radicals, such as hydrogen peroxide (H2O2), can be generated in quantities large enough to overwhelm endogenous protective enzyme systems, such as superoxide dismutase (SOD) and reduced glutathione (GSH) (Slemmer et al., 2008). Several free radical scavengers have been developed and some of them have progressed into clinical trials. One of them, edaravone, has been approved by the regulatory authority in Japan for the treatment of stroke patients.(Wang et al., 2007) The ceria(Chung, 2003) and yttria (Bloor et al., 1994) nanoparticles act as direct antioxidants to limit the amount of reactive oxygen species required to kill the cells and this group of nanoparticles could be used to modulate oxidative stress in biological systems. Several preclinical studies, using a variety of antidepressants, have shown neuroprotective effects but there is a paucity of clinical evidence. In studies on rats, a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of serotonin transporter, and this neuroprotection is detectable in vivo by 4-18 F-ADAM micro-PET (Li et al., 2012)

1.4.3 Antiepileptics

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Some of the currently approved antiepileptic drugs (AEDs) also happen to have a neuroprotective effect. Phenytoin provides neuroprotection and improves functional outcome after experimental spinal cord injury (Hains et al., 2004). Topiramate is shown to prevent excitotoxic brain damage hence can be considered as a candidate therapy for Neuroprotection (Szaflarski et al., 2010).

 

1.4.4 Anti-inflammatory agents

 

            Overexpression of COX-2 appears to be both a marker and an effector of neural damage after a variety of acquired brain injuries, and in natural or pathological aging of the brain. COX-2 inhibitors such as nimesulide and NS-398, acetylsalicylic acid and its metabolite sodium salicylate were found to be protective against neurotoxicity. The site of action of the drugs appears to be downstream of glutamate receptors and to involve specific inhibition of glutamate-mediated induction of nuclear factor kappa B (NF-kB).

Gold microparticles  is used as anti-neuroinflammatory agents. Auromedication by intracerebral application of metallic gold microparticles as a pharmaceutical source of gold ions represents a new medical concept that bypasses the BBB and enables direct drug delivery to inflamed brain tissues (Danscher et al., 2010). The metallic gold treatment significantly increases the expression of the growth factors VEGF, FGF, LIF, and neurotrophin-4 (Pedersen et al., 2010).

1.4.5 Anti-apoptosis agents

Activated protein C (APC), a serine protease with anticoagulant and anti-inflammatory activities, exerts direct cytoprotective effects on endothelium via endothelial protein C receptor-dependent activation of PAR1. Calpain, a primary protease is increased in TBI, cerebral ischemia, SCI, several neuromuscular disorders, and neurodegenerative diseases. Apoptosis can be inhibited by agents that exhibit caspase activity (Zhuang et al., 2009).

1.4.6 Immunophilins

Immunophilin ligands show promise as a novel class of neuroprotective and neuroregenerative agents that have the potential to treat a variety of neurologic disorders. Cyclosporin A (CsA), at therapeutically relevant concentrations, acts directly on neural precursor cells to enhance their survival, both in vitro and in vivo (Sumit et al., 2012).

1.4.7 Glutamate antagonist and modulators

Neuronal death following excessive glutamate-mediated excitation, often referred to as excitotoxicity, is a critical feature of acute cerebral infarction (Kim et al., 2002). Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate are- AP5 (APV, R-2-amino-5-phosphonopentanoate) (Abizaid et al., 2006) AP7 (2-amino-7-phosphonoheptanoic acid) (Van et al., 2002) CPPene (3-(R)-2-carboxypiperazin-4-yl-prop-2-enyl-1-phosphonic acid). NMDAR modulators, including esketamine, rapastinel, NRX-1074, and CERC-301, are under development for the treatment ofmood disorders, including major depressive disorder and treatment-resistant depression (Eblen et al., 1996).

1.4.8 Erythropoietin

Erythropoietin (EPO) and its receptor function as primary mediators of the normal physiological response to hypoxia. Studies in which recombinant human EPO (rhEPO, epoetin alfa) is injected directly into an ischemic rodent brain show that EPO also mediates neuroprotection. Systemic administration of epoetin alfa before or up to 6 h after experimental focal brain ischemia reduces injury by 50–75% (Claudia et al., 2001).

1.4.9 Dexmedetomidine (DMED)

Dexmedetomidine is an ?2 adrenoreceptor agonist which has displayed neuroprotective properties in a variety of in vitro and in vivo laboratory studies. The neuroprotective effects of DMED have been demonstrated in a variety of animal models of ischemia. These include models of incomplete ischemia in the rat, (Hoffman  et al., 1991) transient focal ischemia in rabbits, (Maier  et al., 1993) and transient global ischemia in gerbils. In vitro paradigms of neuronal injury, including those using hippocampal slices and neuronal and cortical cell cultures (Ma  et al., 2014) also support the role of DMED as a neuroprotectant.

1.4.10 Estrogens

Estrogen and progesterone reduce the sequel of the injury cascade by enhancing antioxidant mechanisms, reducing excitotoxicity (altering glutamate receptor activity, reducing immune inflammation, providing neurotrophic support, and stimulating axonal remyelination), and enhancing synaptogenesis and dendritic arborization (Tiwari et al., 2007).

Lazaroids (21?aminosteroids), specifically inhibited lipid peroxidation without glucocorticoid or mineralocorticoid activity, thereby avoiding the complications of corticosteroid therapy. The lazaroids exert their anti?lipid peroxidation action through two mechanisms, free radical scavenging and membrane stabilization (Hall et al., 1989).

1.4.11 Desferoxamine

Deferoxamine is a bacterial siderophore produced by the Actinobacteria Streptomyces pilosus. The iron chelator desferrioxamine (DFO) was used to explore its neuroprotective property against lipopolysaccharide (LPS) induced nigrostriatal degeneration.  The study found that  the iron concentration in the ventral midbrain significantly increased following intrastriatal injection of LPS, and administration of DFO improved behavior deficits, attenuated dopamine (DA) neuron loss and striatal DA reduction, and alleviated microglial activation in the Substantia nigra (Zhang et al., 2012).

1.4.12 Nanoparticles: Fullerene C60

Water-soluble derivatives of buckminsterfullerene C60 derivatives are a unique class of nanoparticle compounds with potent antioxidant properties. Studies on one class of these compounds, the malonic acid C60 derivatives (carboxyfullerenes), indicated that they are capable of eliminating both superoxide anion and H2O2, and were effective inhibitors of lipid peroxidation, as well. Carboxyfullerenes demonstrated robust neuroprotection against excitotoxic, apoptotic, and metabolic insults in cortical cell cultures (Rodríguez et al., 2011).

1.4.13 Magnesium sulphate (MgSO4) in preterm infants

            It is believed that MgSO4 also provides neuroprotection in preterm infants when given to mothers when labor is imminent. Studies suggest that MgSO4 acts as an NMDA (N-Methyl-D-Aspartate) receptor antagonist, reducing the neuronal damage secondary to increased intracellular calcium. Other studies suggest that it prevents neuronal insult by decreasing intrauterine inflammation (Carmen et al., 2011).

1.4.14 Melatonin

Melatonin is a hormone secreted from the pineal gland, levels of which decreased in aging, particularly in AD (Alzheimer’s disease) subjects. This hormone is known to possess neuroprotective properties against beta amyloid toxicity in-vivo. The scavenging of reactive oxygen species by melatonin appears to be the primary effect of melatonin in protecting neurons and astrocytes against beta amyloid toxicity (Ionov et al., 2011).

1.4.15 Neuroglobin

Neuroglobin (Ngb) is an oxygen-binding globins protein that has been demonstrated to be neuroprotective against stroke and related neurological disorders. Accumulating evidence showed that elevated Ngb level is associated with the preserved mitochondrial function, suggesting that Ngb may play neuroprotective roles through mitochondria-mediated pathways (Yu et al., 2013).

1.4.16 Bilirubin

            Bilirubin exhibits potent antioxidant activity and is protective against H2O2-induced free radical damage to neuronal cells in vitro (Doré et al., 2000). It is oxidized back to biliverdin, where it can then be acted upon once again by BVR to regenerate bilirubin. This bilirubin-biliverdin redox loop might explain why bilirubin has such powerful antioxidant effects when it is present in low physiologic concentrations in neuronal cell cultures (Shapiro et al., 2005).

1.4.17 Endogenously produced gas: Hydrogen sulphide (H2S)

H2S is involved in the regulation of (1) intracellular signaling molecules such as protein kinase A, receptor tyrosine kinases, and mitogen kinases, and oxidative stress signaling; (2) ion channels such as calcium (L-type, T-type, and intracellular stores), potassium (KATP and small conductance channels), and cystic fibrosis transmembrane conductance. Regulator chloride channels; and (3) the release and function of neurotransmitters such as GABA, NMDA, glutamate, and catecholamines (Tan et al., 2010).

1.1.18 Neurotrophic factor-Pigment Epithelium-Derived Factor

Pigment epithelium-derived factor (PEDF) has been tested in a postnatal culture model of motor neuron degeneration and shown to be highly neuroprotective. The level of motor neuron choline acetyltransferase (ChAT) was maintained, but not increased, indicating that the observed effect was neuroprotective (Vigneswara et al., 2013).

1.4.19 Colivelin

Colivelin, a neuroprotective peptide, has been constructed by attaching activity-dependent neurotrophic factor (ADNF) to the N-terminus of a potent Humanin derivative, AGA-(C8R) HNG17. Colivelin protects neurons from death relevant to neurodegenerative diseases by activating two independent prosurvival signals: an ADNF-mediated Ca2+/calmodulin-dependent protein kinase IV pathway and an HN-mediated STAT3 pathway.

1.4.20 Herbal agents

Herbs in the Traditional  Medicine that have been documented to have a neuroprotective effect on in vitro and in vivo ischemic model systems, and the neuroprotective compounds produced by them have been isolated. Some of the plants with their reported mechanism of Neuroprotection are as follows-

1.4.20.1 Cardiac glycosides: Neriifolin

A cardenolide glycoside that is digitoxigenin in which the hydroxy group at position 3 has been converted to its (6-deoxy-3-O-methyl-?-L-glucopyranoside derivative found in the seeds of Cerbera odollamand in Thevetia ahouia and Thevitia neriifolia. Neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na+/K+-ATPase is of particular interest because of its known “druggability” (Wang et al., 2006).

1.4.20.2 Flavones-Epicatechin

(-)Epicatechin (epi) is a flavonoid present in cocoa, green tea and red wine. A study was performed on its effects on basic snail behaviors (aerial respiration and locomotion), long-term memory (LTM) formation and memory extinction of operantly conditioned aerial respiratory behavior (Fruson  et al., 2012).

1.4.20.3 Wogonin

Wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of a medicinal herb Scutellaria baicalensis Georgi, was shown to inhibit inflammatory activation of cultured brain microglia by diminishing lipopolysaccharide-induced TNF-? and IL-1?, and suppressing NO production by inhibiting inducible NO synthase (iNOS) induction and NF-kB activation in microglia. Inhibition of the inflammatory activation of microglia by wogonin led to the reduction in microglial cytotoxicity toward cocultured PC12 cells, supporting a neuroprotective role for wogonin in vitro (Lee et al., 2003).

1.4.20.4 Ginseng

American ginseng (Panax quinquefolius) and Asian species of ginseng contain ginsenosides,  which are considered to have several therapeutic properties including antioxidant action. American ginseng, improved the behavioral score and reduced the volume of the striatal lesion in an animal model of neurodegeneration induced by 3-nitropropionic acid, an inhibitor of succinate dehydrogenase (Lian et al., 2005).

1.4.20.5 Parawixin1

Parawixin1, a compound purified from the spider Parawixia bistriata venom stimulates the activity of glial glutamate transporters and can protect retinal tissue from ischemic damage therefore possess neuroprotective activity. Parawixin1 promotes a direct and selective enhancement of glutamate influx by the EAAT2 transporter subtype through a mechanism that does not alter the apparent affinities for the cosubstrates glutamate or sodium (Fontana et al., 2007).

1.4.20.6 Xenon

Xenon is a medical gas performs its anesthetic and neuroprotective functions through binding to the glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor competitively and blocking it. This blockage inhibits the overstimulation of NMDA receptors, thus preventing their following downstream calcium accumulating cascade (Esencan et al., 2013).

 

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