Previously, we have shown that topical application of brain‐derived neurotrophic factor (BDNF) or insulin‐like growth factor 1 (IGF‐1) given within 5 to 30 min after a focal trauma to the rat spinal ...cord attenuates spinal cord injury (SCI)–induced breakdown of the blood–spinal cord barrier (BSCB), edema formation, motor dysfunction, and cell injury. This investigation was undertaken to find out whether a combination of select neurotrophins (BDNF, glial cell line–derived neurotrophic factor GDNF, neurotrophin 3 NT‐3, or nerve growth factor NGF) will further enhance the neuroprotective efficacy of growth factors in SCI. The neurotrophins (0.1–1 μg/10 μL in phosphate‐buffered saline) were applied 30, 60, or 90 min after injury topically over the traumatized spinal cord either alone or in combination. The SCI was performed by making a unilateral incision into the right dorsal horn of the T10–T11 segment under Equithesin anesthesia. The rats were allowed to survive 5 h after trauma. Topical application of BDNF, GDNF, or NGF 30 min after SCI in high concentration (0.5 μg and 1 μg) significantly improved the motor functions and reduced the BSCB breakdown, edema formation, and cell injury seen at 5 h. These beneficial effects of neurotropins were absent when administered separately either 60 or 90 min after SCI. However, a combination of BDNF and GDNF (but not with NT‐3 or NGF) given either 60 or 90 min after SCI significantly reduced the motor dysfunction and spinal cord pathology at 5 h. These novel observations suggest that a select group of neurotrophins in combination have potential therapeutic value for the treatment of SCI in clinical situations.
Human exposure to metal nanoparticles such as silver (Ag), copper (Cu) or aluminum (Al) is very common at work places involving automobile, aerospace industry, gun factories or defense related ...explosives making. Additional sources of exposure to engineered nanoparticles affecting human health are chemical, electronics and communication industries. The nanoparticles (ca. 20 to 120 nm) easily enter the body through inhalation and are deposited into various tissues and organs including brain, where they could stay there for long periods of time. However, the pathophysiological reactions of nanoparticles in vivo on brain function are still not well known. Previous observations from our laboratory showed that engineered nanoparticles from Ag, Cu or Al (50-60 nm) when administered through systemic or intracerebral routes in rats or mice induce neurotoxicity depending on their type, dose and duration of the exposure. These nanoparticles also altered sensory, motor and cognitive functions at the time of development of brain pathologies. Thus, neuronal, glial, axonal and endothelial cell damages are most pronounced following Ag and Cu intoxication as compared to Al in identical doses that are more pronounced in mice as compared to rats of similar age group. The functional significance of these findings and the probable mechanisms of metal nanoparticle-induced neurotoxicity are discussed in this review largely based on our own investigations.
Spinal cord injury (SCI) is a devastating disease that leads to permanent disability of victims for which no suitable therapeutic intervention has been achieved so far. Thus, exploration of novel ...therapeutic agents and nano-drug delivery to enhance neuroprotection after SCI is the need of the hour. Previous research on SCI is largely focused to improve neurological manifestations of the disease while ignoring spinal cord pathological changes. Recent studies from our laboratory have shown that pathological recovery of SCI appears to be well correlated with the improvement of sensory motor functions. Thus, efforts should be made to reduce or minimize spinal cord cell pathology to achieve functional and cellular recovery to enhance the quality of lives of the victims. While treating spinal cord disease, recovery of both neuronal and non-neuronal cells, e.g., endothelia and glial cells are also necessary to maintain a healthy spinal cord function after trauma. This review focuses effects of novel therapeutic strategies on the role of spinal cord microvascular reactions and endothelia cell functions, i.e., blood–spinal cord barrier (BSCB) in SCI and repair mechanisms. Thus, new therapeutic approach to minimize spinal cord pathology after trauma using antibodies to various neurotransmitters and/or drug delivery to the cord directly by topical application to maintain strong localized effects on the injured cells are discussed. In addition, the use of nanowired drugs to affect remote areas of the cord after their application on the injured spinal cord in thwarting the injury process rapidly and to enhance the neuroprotective effects of the parent compounds are also described in the light of current knowledge and our own investigations. It appears that local treatment with new therapeutic agents and nanowired drugs after SCI are needed to enhance neurorepair leading to improved spinal cord cellular functions and the sensory motor performances.
Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of ...brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na
+
indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.
Our knowledge regarding the influence of nanoparticles on brain function in vivo during normal or hyperthermic conditions is still lacking. Few reports indicate that when nanoparticles enter into the ...central nervous system (CNS) they may induce neurotoxicity. On the other hand, nanoparticle-induced drug delivery to the brain enhances neurorepair processes. Thus, it is likely that the inclusion of nanoparticles in body fluid compartments alters the normal brain function and/or its response to additional stress, e.g., hyperthermia. New data from our laboratory show that nanoparticles derived from metals (e.g., Cu, Ag or Al, approximately 50-60nm) are capable of inducing brain dysfunction in normal animals and aggravating the brain pathology caused by whole-body hyperthermia (WBH). Thus, normal animals treated with nanoparticles (for 1 week) exhibited mild cognitive impairment and cellular alterations in the brain. Subjection of these nanoparticle-treated rats to WBH resulted in profound cognitive and motor deficits, exacerbation of blood-brain barrier (BBB) disruption, edema formation and brain pathology compared with naive animals. These novel observations suggest that nanoparticles enhance brain pathology and cognitive dysfunction in hyperthermia. The possible mechanisms of nanoparticle-induced exacerbation of brain damage in WBH and its functional significance in relation to our current knowledge are discussed in this review.
Neurorestorative treatments have been able to improve the quality of life for patients suffering from neurological diseases and damages since the concept of Neurorestoratology was proposed. The ...discipline of Neurorestoratology focuses on restoring impaired neurological functions and/or structures through varying neurorestorative mechanisms including neurostimulation or neuromodulation, neuroprotection, neuroplasticity, neuroreplacement, loop reconstruction, remyelination, immunoregulation, angiogenesis or revascularization, neuroregeneration or neurogenesis and others. The neurorestorative strategies of Neurorestoratology include all therapeutic methods which can restore dysfunctions for patients with neurological diseases and improve their quality of life. Neurorestoratology is different from regenerative medicine in the nervous system, which mainly focuses on the neuroregeneration. It also is different from Neurorehabilitation. Neurorestoratology and Neurorehabilitation share some functional recovering mechanisms, such as neuroplasticity, especially in the early phase of neurological diseases; but generally Neurorehabilitation mainly focuses on recovering neurological functions through making the best use of residual neurological functions, replacing lost neurological functions in the largest degree, and preventing and treating varying complications. Recently, there have been more advances in restoring damaged nerves by cell therapy, neurostimulation/neuromodulation and braincomputer interface (BCI), neurorestorative surgery, neurorestorative pharmaceutics, and other clinic strategies. Simultaneously related therapeutic guidelines and standards are set up in succession. Based on those advances, clinicians should consider injured and degenerated nervous disorders or diseases in the central nervous system as treatable or neurorestorative disorders. Extending and encouraging further neurorestorative explorations and achieving better clinical efficacy with stronger evidence regarding neurorestoratology will shed new light and discover superior benefits for patients with neurological disorders.
Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (AβP), appears to play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Since mesenchymal stem cells (MSCs) and/or ...cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of AβP (1-40) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and AβP concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (10
6
cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of AβP infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 ± 8 pg/g brain) along with a significant decrease in the AβP deposition (45 pg/g from untreated control 75 pg/g; saline control 40 ± 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.
Several neurotrophic factors are known to induce neuroprotection in traumatic injuries to the central nervous system (CNS). However, many neurotrophins are unable to attenuate cell death following ...CNS injuries. New data generated in our laboratory show that a suitable combination of neurotrophic factors may enhance the neuroprotective efficacy of neurotrophins on cell and tissue injury and improve sensory motor functions. This novel aspect of neurotrophins treatment in combination in spinal cord injury (SCI) induced behavioral dysfunctions and spinal cord pathology is examined in a rat model. Our investigations suggest that a suitable combination of neurotrophins will attenuate both neural and non-neural (glial cells and endothelial cells) damage in SCI leading to enhanced neuroprotection. The possible cellular and molecular mechanisms of synergistic effects of some neurotrophins in combination are still speculative and require further investigation.
Recent developments in nanomedicine resulted in targeted drug delivery of active compounds into the central nervous system (CNS) either through encapsulated material or attached to nanowires. ...Nanodrug delivery by any means is supposed to enhance neuroprotection due to rapid accumulation of drugs within the target area and a slow metabolism of the compound. These two factors enhance neuroprotection than the conventions drug delivery. However, this is still uncertain whether nanodrug delivery could alter the pharmacokinetics of compounds making it more effective or just longer exposure of the compound for extended period of time is primarily responsible for enhanced effects of the drugs. Our laboratory is engaged in understanding of the nanodrug delivery using TiO2 nanowires in CNS injuries models, for example, spinal cord injury (SCI), hyperthermia and/or intoxication of nanoparticles with or without other comorbidity factors, that is, diabetes or hypertension in rat models. Our observations suggest that nanowired drug delivery is effective under normal situation of SCI and hyperthermia as evidenced by significant reduction in the blood–brain barrier (BBB) breakdown, brain edema formation, cognitive disturbances, neuronal damages, and brain pathologies. However, when the pathophysiology of these CNS injuries is aggravated by nanoparticles intoxication or comorbidity factors, adjustment in dosage of nanodrug delivery is needed. This indicates that further research in nanomedicine is needed to explore suitable strategies in achieving greater neuroprotection in CNS injury in combination with nanoparticles intoxication or other comorbidity factors for better clinical practices. WIREs Nanomed Nanobiotechnol 2012, 4:184–203. doi: 10.1002/wnan.172
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease
Functional restoration after spinal cord injury (SCI) is one of the most challenging tasks in neurological clinical practice. With a view to exploring effective neurorestorative methods in the acute, ...subacute, and chronic phases of SCI, “Clinical Therapeutic Guidelines of Neurorestoration for Spinal Cord Injury (China Version 2016)” was first proposed in 2016 by the Chinese Association of Neurorestoratology (CANR). Given the rapid advances in this field in recent years, the International Association of Neurorestoratology (IANR) and CANR formed and approved the “Clinical Neurorestorative Therapeutic Guidelines for Spinal Cord Injury (IANR/CANR version 2019)”. These guidelines mainly introduce restoring damaged neurological structure and functions by varying neurorestorative strategies in acute, subacute, and chronic phases of SCI. These guidelines can provide a neurorestorative therapeutic standard or reference for clinicians and researchers in clinical practice to maximally restore functions of patients with SCI and improve their quality of life.
This guideline provided comprehensive management strategies for SCI, which contains the evaluation and diagnosis, pre-hospital first aid, treatments, rehabilitation training, and complications management. Nowadays, amounts of neurorestorative strategies have been demonstrated to be benefit in promoting the functional recovery and improving the quality of life for SCI patients by clinical trials. Also, the positive results of preclinical research provided lots of new neurorestorative strategies for SCI treatment. These promising neurorestorative strategies are worthy of translation in the future and can promote the advancement of SCI treatments.
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