MS is an autoimmune demyelinating disease with a neurodegenerative component most commonly diagnosed in patients 20 - 40 years of age [10]. In MS, the immune system attacks the white matter of the brain and spinal cord, causing multifocal demyelination leading to disability and/or paralysis. In acute MS, oligodendrocytes die mainly by apoptosis, however, in chronic MS lesion apoptosis was absent or rare which could because of the rapid removal of apoptotic cells in vivo [11]. Oxidative stress plays an important role in oligodendroglial death in MS [12]. Macrophages from MS patients show increased production of superoxide radicals and H₂O₂; while CSF displays significantly high level of NO metabolites, nitrite and nitrate compared to controls [13]. As the MS lesion formation starts, locally produced ROS induce tight junction and cytoskeletal changes in brain endothelial cells which facilitate transendothelial monocyte migration [6]. ROS also has a critical role in myelin phagocytosis and it has been observed that using ROS inhibitors like NADPH oxidase inhibitors, lipoic acid or catalase enzyme reduced myelin phagocytosis by macrophages [6]. Excitatory glutamate levels are increased in acute MS lesions and in normal-appearing white matter in MS patients [14]. In addition, oxidative stress contributes to the increase in glutamate concentrations in the extracellular space, as free radicals reduce the efficiency of GluTs [14]. TNF-α is found at high levels in multiple sclerosis (MS) plaques and induces both apoptotic and necrotic death of OLGs and inhibition of caspase-1 and caspase-3 protects them against TNF-α-induced apoptosis [11]. Interferon gamma (IFN-γ) produced by lymphocytes in MS lesions plays a role in apoptosis of oligodendrcoytes both in vivo and in vitro [11]. TNF-α increases the IFN-γ-induced death of OPCs and this effect can be partially suppressed by caspase inhibition [11]. Interleukin-11 is expressed by reactive astrocytes in MS tissue samples along the myelinated border of both active and silent lesions [15].

Paraventricular leukomalacia (PVL) is the leading cause of brain damage in preterm infants, prior to 32 weeks of gestation; resulting in cerebral palsy and cognitive impairment [16,17]; and occurs due to damage to OPCs and hypomyelination [18]. It involves death of small areas of brain tissue around ventricles, the fluid filled areas of brain; creating holes in the brain [19]. The pathogenesis of OPC injury relates to hypoxia-ischemia and systemic infection/inflammation, common occurrences in premature infants. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack [20].

Stroke, a leading cause of death occurs due to the interruption of blood supply to any part of the brain owing to the blockade or bursting of blood vessels, hence classified as ischemic and hemorrhagic stroke [21]. Immediately following interrupted blood supply to brain, the injury process initiates, if recovery of normal blood flow is not achieved within a short period of time, death of cells within the ischemic core begins [22]. Stroke disrupts the blood brain barrier (BBB) which in turn affects stroke progression and neuroregeneration [23]. Ischemia, in stroke, is known to cause cell death mainly through the oxidative stress and excitotoxicity. Energy deprivation in stroke leads to neuronal death, axonal dysfunction and loss of OLGs which are very sensitive to transient oxygen and glucose deprivation. It has been seen that OLGs in immature state are even more sensitive to ischemic injury in mature forms. These cells may release glutamate under ischemic conditions by reverse functioning of their glutamate transporter (GluTs) [14]. During ischemia/ reperfusion of brain tissue, oxidative stress sets in with a rise in Hydrogen Peroxide (H₂O₂) levels for about 1hr reaching up to 175 μM (approx.) [14]. Also, increased TNF-mRNA is seen 3 hr after stroke in transient Middle cerebral artery occlusion (MCAO) models in rats [23].

In humans, almost all cases of ischemic stroke involve white matter [24]. White matter ischemia may activate proteases like calpains which degrade neurofilament and cause phosphorylation of axonal microtubule proteins like tau. Thereby, they weaken the structural integrity of axons and also impair axonal mechanisms for anterograde and retrograde transport [25].

Spinal cord injury (SCI) refers to the damage to the spinal cord resulting in permanent neurological deficit. It is caused by direct injury or indirectly from damage to the surrounding bones, tissues, or blood vessels resulting from auto accidents, falls, sports injuries and other accidents. It is a very tragic case with higher prevalence in young and otherwise healthy individuals, thus creating physical, emotional, and economic burdens on both sufferer and society [26]. The loss of axonal transmission of sensory and motor nerves occurs distal to point of SCI, leading to multiple health problems such as recurrent kidney stones, urinary tract infection, pressure sores, and cardiac and respiratory dysfunction [27]. Acute SCI involves mechanical primary and biochemical secondary mechanism of injury; primary due to blunt cord compression owing to dislocation of spinal cord or bone fragments; biochemical factors in hemorrhagic necrotic tissue causing secondary damage to spinal cord [28]. SCI causes strong up-regulation of genes involved in transcription, inflammation and cell death [29]. Excitotoxicity, oxidative stress, lipid peroxidation/free radical injury, inflammatory factors all seem to play parts worsening the homeostasis of the brain and causing cell death [28].

Leukodystrophies are rare diseases appearing during infancy or childhood and characterized by a progressive degeneration of the white matter due to imperfect growth or development of the myelin sheath [30]. Myelin is a complex framework made up of at least ten different chemicals. The leukodystrophies are a group of disorders caused by genetic defects in how myelin produces or metabolizes its chemicals components [4]. Each type of leukodystrophy results from the defect in the gene that controls one of the chemicals causing defects in enzymes such as arylsulphatase A (Metachromatic Leukodystrophy), aspartoacylase (Canavan disease), galactosylceramidase (Krabbe disease) or in enzymes responsible for breaking down phytanic acid (Refsum’s disease), defects in a fatty acid transfer protein (Adrenoleukodystrophy), or defects in the myelin protein PLP1 (Pelizaeus-Merzbacher disease) [31].

AD is a neurodegenerative disease with stealth onset that progresses relatively rapidly with the parenchymal deposition of beta amyloid (Aβ) in the form of senile/neuritic plagues and the neurofibrillatory tangles (NFT) resulting in the loss of neurons and synapses [32]. The white matter lesions and myelin abnormalities are common in the AD patients [33]. A is known to induce apoptosis of mature OLGs which can be attenuated by antioxidants. A also causes oxidative stress by upregulation of inducible nitric oxide synthase (iNOS) in mature OLGs through a TNF-α-mediated ceramide pathway [32]. Some cases of AD are caused by mutation of presenilin-1 gene. It has been seen that glutamate-mediated excitotoxicity in OLGs is potentiated by presenilin-1 mutation [31]. OLGs that differentiate and myelinate later in life produce thinner myelin sheaths around axons and these neurons have been observed to be more susceptible to the damage in AD [32]. The transentorrhinal region and nearby neocortical association areas are the late-myelinating regions known; these areas are also the seat for early Aβ deposits and myelin breakdown [5].

Schizophrenia is a complex mental disorder of unknown etiology, usually surfacing in the young adulthood, which carries a genetic link [34]. Neuroimaging and microarray studies have provided evidence for myelin and oligodendrocyte abnormalities in SZ. As evidenced from electron microscopy, OLGs are the most severely affected cells in SZ undergoing dystrophy, necrosis and apoptosis [35]. Decreased expression of myelin and oligodendrocyterelated genes is seen in postmortem samples obtained from prefrontal cortex regions of schizophrenic patients, suggesting OLG loss or disruption at functional levels [36]. Six myelin-related genes specific to OLGs have decreased expression levels in schizophrenia. OLGs are decreased in number in the superior frontal gyrus of schizophrenics. Absence of myelin associated glycoprotein (MAG) genes may be the link in schizophrenia since MAG-knockout mice develops as a mice model for the disease [37]. Abnormal glutamate homeostasis is considered one of the leading pathological mechanisms of schizophrenia and this also puts OLGs at increased risk for excitototic damage [38]. Abnormalities in the white matter have been observed; however, so far it is not clear whether it is a cause or a consequence of the disease [32].

Oligodendrocytes are also injured in a variety of other diseases like Progressive Multifocal Leukoencephalopathy [7], Post-Infectious Encephalitis [39], and also following radiation injury [40], etc.

OLGs on exposure to reactive oxygen species (ROS) causes formation of lipid peroxides which further react with proteins leading to oxidative modifications of amino acid residue. Also the protein aggregates are formed and protein fragmentation occurs [41], and also leads to DNA fragmentation and finally apoptosis of cells. H₂O₂, a ma jor ROS, is normally produced in the brain in small amounts. Its toxicity is due to its reaction with transition metals (iron-mediated Fenton reaction) to form hydroxyl radicals, which can further react with amino acids, nucleic acids, phospholipids and sugars, eventually causing cell death [42].

Oligodendrocytes injury and death occurs on exposure to excitotoxic agents like glutamate and extraceullular ATP [14]. Mature OLGs undergo necrosis on exposure to kainite through the Alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA), and kainite (KA) receptors; recently N-methyl-D-aspartate (NMDA) have also been known to play role in OLG pathology [43,44]. Oka et al. was the first to provide evidence that OLGs are highly vulner able to glutamate using the primary cultures. The oligodendroglial toxicity is mediated by a transporter-related mechanism involving the inhibition of cystine uptake, which results in glutathione depletion and cellular vulnerability to toxic-free radicals. Glutamate

can also cause glial death indirectly by inducing the release of toxic agents like TNF-α from microglia [14].

Cytokines, a family of proteins related to immune system, are known to cause oligodendrocyte injury accompanying autoimmunological pathology; studies have mainly focused on TNF-α, IFN-γ and Interleukin-1β (IL-β). TNF-α produced by immune system cells and by neurons, astrocytes and microglia. It induces both apoptotic and necrotic death of OLGs and inhibition of caspase-1 and caspase-3 protects them against TNF-α-induced apoptosis [11]. Mutations or breakages in mitochondrial DNA, damage to oligodendrocyte mitochondria or inhibition of oxidative metabolism could also deplete the supply of energy for biosynthesis of the components of mature membrane sheets and/or trigger oligodendroglial degeneration [45]. TNF-α regulates glutamate transport capacity in astrocytes, which leads to the accumulation of glutamate, increasing excitotoxic damage to OLGs and neuron [46]. TNF-α pro-apoptotic actions on OLGs are attributed to decreased IGF-1 expression and activity which can be rescued for external application of IGF-1 both in vivo and in vitro [11]. TNF-α may directly damage OLGs by forming peroxides of the long-chain fatty acids in lipids or via generation of ceramide which is cytotoxic to OLGs [47]. IFN-γ produced by lymphocytes in MS lesions plays a role in apoptosis of oligodendrcoytes both in vivo and in vitro. TNF-α increases the IFN-γ induced death of OPCs and caspase inhibition partially suppresses it [11]. IL-1β, a prominent microglial pro-inflammatory cytokine adversely affects oligodendrocyte survival. It is a potent regulator of the production of various matrix metalloproteinase (MMP) members which are implicated in demyelination and axonal loss in CNS diseases [48].

Minocycline, a second-generation tetracycline, has shown beneficial effects in a wide range of acute neurological injuries. In rodent brain ischemic models, it showed anti-inflammatory effects by inhibiting immune mediators such as microglia. It has shown to attenuate hypoxia/ ischemia-induced white matter injury in the neonatal rat though report of directly protecting OLGs against ischemic stress in adult rodent stroke model is missing. It has also been seen that delayed minocycline treatment reduced long-term functional deficits as well as white matter injury in ET-1-induced rat ischemia model. Despite reports from animal models clinical trial using mino cycline in Amyotrophic lateral sclerosis (ALS) patients, failed to show efficacy, this could be attributed to the long term use of minocycline, a powerful metalloproteinase inhibitor. It has been suggested that long-term suppression of metalloproteinases may be detrimental for neurovascular homeostasis [49].

Antioxidants and free radical scavengers have proved beneficial to OLGs which show a great vulnerability to oxidative stress. Body’s endogenous component and various synthetic drugs have been tried for use in preventing damage to OLGs and a few of them which proved beneficial have been listed below.

It has been shown that infusion of human umbilical cord blood cells protects striatal white matter tracts in vivo and directly protects mature primary oligodendrocyte cultures from oxygen glucose deprivation (OGD) [55].

Different endogenous factors secreted in animals have positive influences in OLGs. The PDGF, basic-fibroblast growth factor (b-FGF), and IGF-1 are known to influence oligodendrocyte lineage cell proliferation and survival [64]. A few of these endogenous factors have shown to afford protection to the OLGs against different stress conditions. The promising results from endogenous factors have been listed below.

Glutamate excitotoxicity related death of oligodendrocyte is seen in many disease states and thus exploiting the receptor antagonists have proved to be beneficial in different experiments. The antagonists of AMPA/KA and NMDA receptor types associated with glutamate signaling have shown significant reduction of OLG death in hypoxia/ischemia models. Hence, they may prove beneficial targets for prevention of ischemic stroke and related OLG deaths.

Even the hormones like erythropoietin and melatonin have proved beneficial in improving recovery of injured white matter through increased oligodendrogenesis and through reduction of oxidative stress. Also thyroxine is considered to be vital for survival of OLGs and it is known to trigger the maturation process of OLGs [69].

Heat shock protein 90 (HSP90) present in OPCs surface has been known to form autoantibodies in Multiple Sclerosis. HSP90 inhibitors radicicol and 17-allylamino- 17-demethoxygeldanamycin (17-AAG) at non-cytotoxic doses target cell-surface HSP90 in OPCs and through competitive inhibition of receptors prevent HSP90-antibody-induced OPC death thus protecting them against antibody attack. They also have shown protective effect on adult OLGs [57].

Bao et al. using primary cultures of rat glial cells showed that a synthetic immunomodulator linomide prevents OLGs damage by suppressing nitric oxide production in microglia and astrocytes [58].

Ischemic injury in the gray matter is associated with excitatory amino acid neurotransmitters release, and in the white matter is associated with intracellular sodium accumulation. The effect of sodium channel blocking drugs phenytoin, carbamazepine and diazepam on anoxia-induced injury in CNS white matter in vitro rat optic nerve preparation has shown to offer protection against anoxic injury at concentrations much lower than that required for treating epilepsy [63]. Sodium channel blockers represent an attractive therapeutic target because of their ability to simultaneously interfere indirectly with several calcium sourcing pathways [71].