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Role of Oxidative Stress in Neurodegeneration
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Neelam Yadav, Pradeep K. Shukla
Free radical spin traps are compounds that react with free radicals to form more stable adducts. They can, therefore, serve as free radical scavengers (Scott, Billiar, and Stoyanovsky 2016). They are effective in attenuating both eye-related oxidative damage to proteins and ischemic lesion in vivo (Oshida, Matsumoto, and Arai 2010; Floyd et al. 2013). The synthesized free radical scavengers seem to be very potent in the medium during the hypoxic period (Gassen and Youdim 1999). Free radical formation is a relatively late phenomenon and is believed to have a long-lasting effect with a peak potential when fresh oxygen is supplied. This may partially explain the large effect of scavenger when compared to, for example, the effect of nimodipine that affects the entry of calcium via L-channels for a relatively short period. The fact that both scavengers have a significant effect indicates that the highly lipophilic 21-amino steroid (Hall, McCall, and Means 1994). This is of importance as it is now known that tirilazad mesylate, which is highly efficient in protecting neurons in tissue culture, probably does not reach neuron in vivo due to its extreme lipophilicity. The high neuroprotective potential of tirilazad mesylate in vivo can be explained by its action on the endothelium of the brain capillary bed (Hall and McCall 1994).
The Discovery and Pharmacology of Tirilazad Mesylate
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Tirilazad mesylate has been evaluated in many models of injury to the CNS: head and spinal cord injury, ischemia, and hemorrhagic stroke. The drug is optimally given by the i.v. route. In a mouse head injury model, Hall et al.8 showed that tirilazad mesylate significantly improved the 1-h post injury neurological status (grip test score) of mice with severe concussive head injury when given by a single i.v. dose over a broad dose range (0.003 to 30.0 mg/kg). The 1-h postinjury neurological status (grip test score) increased by as much as 168.6% relative to control. A 1-mg/kg i.v. dose, given within 5 min and again at 1.5 h after a severe injury, not only improved early recovery, but also significantly increased the one-week survival rate to 78.6% compared with 27.3% in vehicle-treated mice (see Figure 4). Methylprednisolone sodium succinate also promoted early neurological recovery in severely head-injured mice, although the degree of improvement was less than that achieved using tirilazad mesylate.8
Neuroprotection and repair after spinal cord injury
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
The pathophysiology of spinal cord injury (SCI) has generated significant research interest, and many attempts to limit injury (neuroprotection), improve regeneration, or augment the function of surviving tissue (neuroaugmentation) have met success in animal models. Four neuro-protective agents and one neuroregenerative compound have progressed to phase III clinical trials.1–5 Despite their initial promise, none have demonstrated convincing efficacy. The American Association of Neurological Surgeons and Congress of Neurological Surgeons Joint Section on Disorders of the Spine and Peripheral Nerves’ 2012 Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injury therefore do not recommend the use of either neuroprotective or neuroregenerative therapies following acute SCI.6 Further, the guideline statement cautions against the use of methylprednisolone as insufficient Class I evidence exists to support its purported benefits while harmful side effects including death have been consistently observed (level 1 recommendation). In the case of GM-1 ganglioside (monosialotetrahexosylganglioside), the available literature suggests no clinical benefit is associated with its use and therefore the administration of GM-1 ganglioside is not recommend in the acute treatment of SCI (level 1 recommendation). Tirilazad, nimodipine, and naloxone have been studied but without sufficient evidence of efficacy to warrant inclusion in the guidelines.
Citation analysis of the most influential articles on traumatic spinal cord injury
Published in The Journal of Spinal Cord Medicine, 2020
Ronak H. Jani, Arpan V. Prabhu, James J. Zhou, Nima Alan, Nitin Agarwal
Year-by-year citation frequency for the top five most highly cited articles is depicted in (Fig. 4). Hochberg et al., which reported neuro-prosthetic use by a person with tetraplegia, peaked at 185 citations in 2009, declining slightly since but remaining highly referenced in 2016 with 127 citations.22 Bracken et al.20 (NASCIS 2) and Bracken et al.23 (NASCIS 3), comparing methylprednisolone administered over 24 h, methylprednisolone administered over 48 h, and treatment with tirilazad mesylate have maintained relatively steady numbers of citations since the initial five years post-publication.20, 23 Colombo et al., describing a robotic driven gait orthosis to assist treadmill training rehabilitation, experienced steadily increasing citation frequency until 2008 and has since been cited at a steady rate.24 Finally, citations per year of Anderson et al., a survey-based study reporting individuals’ highest priority functional goals after SCI, have continued to climb since publication in 2004 and have not appeared to reach a plateau as of 2016.25
A mechanistic overview of spinal cord injury, oxidative DNA damage repair and neuroprotective therapies
Published in International Journal of Neuroscience, 2023
Jaspreet Kaur, Aditya Mojumdar
One of the major pharmacological targets is the step of oxidation post-SCI, making antioxidants as potential neuroprotective agents. For decades, antioxidants have been studied as neuroprotective agents, such as - reduced glutathione administered intravenously [132], Vitamin E (α-tocopherol which is an active free radical scavenger) treatment [133], Methylprednisolone (MP, glucocorticoid steroid, reviewed in Hall and Springer, 2004 [134]), Tirilazad (non-glucocorticoid 21-aminosteroid, reviewed in Hall and Springer, 2004 [134]), Penicillamine and Tempol (antagonists of lipid peroxidation) [135,136], and BN-80933 (dual-inhibitor of lipid peroxidation and nitric oxide synthase) [137], have been reported to show neuroprotective benefits.