Hermelinda Salgado-Ceballos

Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases

Abstract Aging and neurodegenerative diseases share oxidative stress cell damage and depletion of endogenous antioxidants as mechanisms of injury, phenomena that are occurring at different rates in each process. Nevertheless, as the central nervous system (CNS) consists largely of lipids and has a poor catalase activity, a low amount of superoxide dismutase and is rich in iron, its cellular components are damaged easily by overproduction of free radicals in any of these physiological or pathological conditions. Thus, antioxidants are needed to prevent the formation and to oppose the free radicals damage to DNA, lipids, proteins, and other biomolecules. Due to endogenous antioxidant defenses are inadequate to prevent damage completely, different efforts have been undertaken in order to increase the use of natural antioxidants and to develop antioxidants that might ameliorate neural injury by oxidative stress. In this context, natural antioxidants like flavonoids (quercetin, curcumin, luteolin and catechins), magnolol and honokiol are showing to be the efficient inhibitors of the oxidative process and seem to be a better therapeutic option than the traditional ones (vitamins C and E, and β-carotene) in various models of aging and injury in vitro and in vivo conditions. Thus, the goal of the present review is to discuss the molecular basis, mechanisms of action, functions, and targets of flavonoids, magnolol, honokiol and traditional antioxidants with the aim of obtaining better results when they are prescribed on aging and neurodegenerative diseases.

Efficacy and Safety of 4-Aminopyridine in Patients with Long-Term Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

Objectives. To study the efficacy and safety of 4‐aminopyridine (4‐AP), and to document sensorimotor changes after discontinuation of the drug in patients with long‐term spinal cord injury.

Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats

Although dapsone (4,4′‐diaminodiphenylsulfone) has been described as a neuroprotective agent in occlusive focal ischemia in rats, its mechanism of action is still unknown. To explore this mechanism, oxidative, inflammatory and apoptotic processes were evaluated in the striatum of adult rats using a model of ischemia‐reperfusion (I/R), either with or without dapsone treatment. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2 hr, followed by reperfusion. Rats were dosed either with dapsone (12.5 mg/kg i.p.) or vehicle 30 min before or 30 min after the ischemia onset. Lipid peroxidation (LP) and nitrotyrosine contents were measured 22 hr after reperfusion, and myeloperoxidase activity was evaluated 46 hr after I/R. Different markers for apoptosis and necrosis were also evaluated both at 24 and 72 hr after I/R experimental procedure. LP increased by 37% in ischemic animals vs controls, and this effect was reversed by dapsone treatments. A similar effect was observed regarding nitrotyrosine striatal contents. Myeloperoxidase activity, a marker of inflammatory response, increased 3.7‐fold in ischemic animals vs. control rats, and dapsone treatment antagonized that effect. Although apoptosis was increased by the effect of ischemia at both evaluation times, dapsone antagonized that effect only at 72 hr after surgery. Dapsone antagonized all of the I/R end points measured, showing a remarkable ability to decrease markers of damage through antioxidant, antiinflammatory, and anti‐apoptotic effects.

Early metabolic reactivation versus antioxidant therapy after a traumatic spinal cord injury in adult rats.

Disability after traumatic spinal cord injury (TSCI) results from physical trauma and from “secondary mechanisms of injury” such as low metabolic energy levels, oxidative damage and lipid peroxidation. In order to prove if early metabolic reactivation is a better therapeutic option than antioxidant therapy in the acute phase of TSCI, spinal cord contusions were performed in adult rats using a well‐characterized weight drop technique at thoracic 9 level. After TSCI, pyrophosphate of thiamine or non‐degradable cocarboxylase (NDC) enzyme was used to maintain energy levels, antioxidants such as superoxide dismutase and catalase (ANT) were used to decrease oxidative damage and methylprednisolone (MP), which has both therapeutic properties, was used as a control. Rats were divided into one sham group and six with TSCI; one of them received no treatment, and the rest were treated with NDC, MP, NDC + MP, NDC + ANT or ANT. The ANT group decreased lactate and creatine phosphokinase levels and increased the amount of preserved tissue (morphometric analysis) as well as functional recovery (Basso, Beattie and Bresnahan or BBB motor scale). In contrast, NDC treatment increased lipid peroxidation, measured through thiobarbituric acid reactive substances (TBARS) levels, as well as spinal cord tissue destruction and functional deficit. Early metabolic reactivation after a TSCI may be deleterious, while natural early metabolic inhibition may not be a “secondary mechanism of injury” but a “secondary neuroprotective response”. While increased antioxidant defence after a TSCI may currently be an ideal therapeutic strategy, the usefulness of metabolic reactivation should be tested in the sub‐acute or chronic phases of TSCI and new strategies must continue to be tested for the early ones.

Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury.

After spinal cord injury (SCI), a complex cascade of pathophysiological processes increases the primary damage. The inflammatory response plays a key role in this pathology. Recent evidence suggests that myeloperoxidase (MPO), an enzyme produced and released by neutrophils, is of special importance in spreading tissue damage. Dapsone (4,4′‐diaminodiphenylsulfone) is an irreversible inhibitor of MPO. Recently, we demonstrated, in a model of brain ischemia/reperfusion, that dapsone has antioxidant, antiinflammatory, and antiapoptotic effects. The effects of dapsone on MPO activity, lipid peroxidation (LP) processes, motor function recovery, and the amount of spared tissue were evaluated in a rat model of SCI. MPO activity had increased 24.5‐fold 24 hr after SCI vs. the sham group, and it had diminished by 38% and 19% in the groups treated with dapsone at 3 and 5 hr after SCI, respectively. SCI increased LP by 45%, and this increase was blocked by dapsone. In rats treated with dapsone, a significant motor function recovery (Basso‐Beattie‐Bresnahan score, BBB) was observed beginning during the first week of evaluation and continuing until the end of the study. Spontaneous recovery 8 weeks after SCI was 9.2 ± 1.12, whereas, in the dapsone‐treated groups, it reached 13.6 ± 1.04 and 12.9 ± 1.17. Spared tissue increased by 42% and 33% in the dapsone‐treated groups (3 and 5 hr after SCI, respectively) vs. SCI without treatment. Dapsone significantly prevented mortality. The results show that inhibition of MPO by dapsone significantly protected the spinal cord from tissue damage and enhanced motor recovery after SCI.

Plasma polypyrrole implants recover motor function in rats after spinal cord transection

We studied the use of three biocompatible materials obtained by plasma polymerization of pyrrole (PPy), pyrrole doped with iodine (PPy/I) and a copolymer formed with pyrrole and polyethylene glycol (PPy/PEG), implanted, separately, after a complete spinal cord transection in rats. Motor function assessed with the BBB scale and somatosensory evoked potentials (SEPs) in the implanted rats were studied. Results showed that the highest motor recovery was obtained in rats with PPy/I implants. They also showed a significant reduction in the latency of SEPs. Histological analyses showed no signs of implant rejection; on the contrary, implants based on PPy improved the SEPs conduction and motor function after lesion.

Anticonvulsive effect of vitamin C on pentylenetetrazol-induced seizures in immature rats ☆

Vitamin C helps to prevent brain oxidative stress and participate in the synthesis of progesterone. It also possesses a progesterone-like effect and acts synergistically with progesterone on the brain. Progesterone and its metabolites, but also vitamin C have been associated with anticonvulsant effects. We evaluated the progesterone concentration 30min and 24h after the last administration of vitamin C (500mg/kg, i.p. for five days). We also evaluated how vitamin C altered pentylenetetrazol (PTZ)-induced seizures by measuring the onset latency of seizures, percentage of incidence and mortality as well as amino acid levels after seizures. Vitamin C treatment alone increased basal progesterone concentrations to 531% after 30min compared to 253% after 24h. Furthermore, vitamin C significantly increased the latency to the first myoclonic, clonic and tonic seizure induced by PTZ (80mg/kg, i.p.) and decreased the percentage of incidence of clonic and tonic seizures as well as the mortality rate. Changes in tissue concentration of amino acids were primarily observed at 24h after vitamin C treatment. Our results suggest that vitamin C together with progesterone and/or its metabolites are involved in the protection against PTZ-induced seizures in immature rats.

Neuroprotection of completely lacerated spinal cord of adult rats by homotopic and heterotopic transplantation

To evaluate the neuroprotective effect of transplants placed in the lesion zone after a complete spinal cord (SC) laceration, two independent series of experiments were carried out. In the first, allogeneic or xenogeneic fetal SC was transplanted into the gaps of the damaged lower thoracic SC of adult rats. In the transplanted rats the incidence of life-threatening complications was reduced, and the survival rate was increased compared with the control group (lesion, without implant). Histological examination showed less damage to the neighboring SC parenchyma in the transplanted rats. The measurement of this neuroprotective effect was made in a second series of experiments. Using the same model of SC injury, allogeneic fetal SC, autologous peripheral nerve and/or adipose tissue were implanted. Rats with implants of Gelfoam and damaged rats without implants were the controls. The implanted rats of all groups, including the Gelfoam group, showed a better survival rate than the nonimplanted rats. Significantly less damage to the neighboring SC parenchyma was measured in implanted rats with any of the live tissues tested compared with non-implanted rats, although no significant differences were observed between the Gelfoam group and the nonimplanted rats. Histological evidence of tissue implant survival was observed in all corresponding groups. It is concluded that the transplanted tissues tested here have a neuroprotective effect, possibly by acting as a buffer to neurotoxic substance(s) released by the stumps, and/or by exerting trophic effect(s) on the host.

Spontaneous and induced aberrant sprouting at the site of injury is irrelevant to motor function outcome in rats with spinal cord injury.

In the absence of effective regeneration following spinal cord (SC) injury, sprouting from undamaged axons has been regarded as an underlying factor for functional improvement after incomplete SC injury. The influence of spontaneous and induced axonal sprouting at the injury site on motor function was tested using rats subjected to moderate SC contusion at T9 level, using megadoses of methylprednisolone (MP) and intralesion implantation of cells from sciatic nerve (PNI). Groups using MP and PNI combined, implant vehicle, and injury with no treatment were also included. Amount of sprouting at the injury sites was significantly different depending on treatment. It was abundant in PNI-treated rats, moderate in rats treated with vehicle or nontreated, and limited in rats given MP with or without PNI (chi2, p=0.0084). This sprouting showed an aberrant course and was located in proliferating tissue at the site of injury, characterized by the presence of ependymal cells, macrophages, and myelinating and nonmyelinating Schwann cells. Functional scores and amount of spared white matter were not significantly different among groups. Correlation of the amount of sprouting vs. functional outcome or vs. amount of spared tissue was not significant, while correlation of functional outcome vs. amount of spared tissue was significant (p<0.0001). In conclusion, PNI increase aberrant sprouting at the injury site, while MP limits such sprouting, in either case without impact on motor function outcome. Missing guiding channels for sprouting axons could explain the absence of any functional improvement.

Stereolithography in spine pathology: a 2-case report

BACKGROUND Solid plastic replicas of anatomical structures obtained by stereolithography from computed tomographic images and magnetic resonance imaging are being used as complementary tools for diagnostic purposes and therapy planning for diverse pathologies. CASE DESCRIPTIONS Case 1--The spine mold of a 62-year-old man with neurologic compromise secondary to degenerative cervical disease was used to study the pathologic features of his spine and to plan and simulate the approach to remove osteophytes before surgery. Also, by examining the replica of his spine, the unconvinced patient was able to understand the nature of his pathology and realize that his neurologic symptoms would disappear only through surgery, as they did. Case 2--A 27-year-old woman had uncontrolled back and leg pain possibly related to anxiety and depression. She had undergone one unsuccessful lumbo-sacral surgery and was now obsessed with the thought that her second surgery, performed by us, likewise had failed, even though her magnetic resonance images proved otherwise. It was not until she held a replica of her repaired spine in her hands that she was able to understand that her pain was unfounded. Once she was able to relax, her chronic pain and anxiety disappeared within a month, using the same antidepressive treatment that formerly had been ineffective. CONCLUSIONS Spine replicas are useful devices for diagnosis, planning, and simulating surgery, and they enable patients to understand the nature of their pathologies and the surgical procedures at hand.