CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 11, Issue 1, 2012

In 2012 CNS & Neurological Disorders - Drug Targets will enter its 11th year of publication. This year will also mark my third year as Editor-in-Chief. Since taking the helm of the journal a number of changes have been introduced, one of my first having been to renew and expand our Editorial Advisory Board to include a broader base of expertise in this incredibly fast-moving area of science. Starting last year, and continuing in 2012 CNS & Neurological Disorders - Drug Targets expands its production calendar to 8 issues per year, up from the previous frequency of 6 issues. Other developments, which I believe will strengthen interest in the journal and encourage an increasingly diverse range of topic submissions is the inclusion, apart from reviews, of both full-length and letter-type research articles as well as clinical case reports. We have added also sections dealing with short Research Highlights discussing recent, high impact publications of relevance to the journal's mission together with reports on meetings. A number of cutting-edge Hot Topic issues are in the works for 2012, including nanoneuroscience, endocannabinoids, novel strategies for neuropsychiatric disorders, and purinergic receptor signaling. CNS & Neurological Disorders - Drug Targets is always open to theme issue proposals from our readers, and I encourage you to submit your ideas for consideration. With best wishes for a productive New Year,

The Italian Society of Neurology (SIN), founded in 1907, held its 42nd national meeting in Turin, Italy during October 2011. The Society, currently numbering more than 3000 members, represents the largest gathering of clinical-oriented neurological sciences in Italy. This SIN meeting coincided with the 150th anniversary of the Unity of Italy, in a city that once served as the country's capital. The meeting offered a number of workshops, courses, and translational science opportunities, together with plenary lectures given by internationally-recognized opinion leaders. In addition, the national meeting continues to place increasing emphasis on allowing young investigators and students to communicate their research findings. Although space does not permit, a few highlights are briefly discussed below. Four symposia were dedicated to multiple sclerosis (MS). MS is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is estimated that there are about 2 million MS patients worldwide: it constitutes the most common non-traumatic neurological disorder among young adults. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Although there is no known cure for MS, magnetic resonance imaging now allows for the quantification of tissue damage caused by macroscopic lesions as well as apparently normal tissue. Quantitative magnetic resonance imaging is capable of providing information also on the biochemical nature of structural alterations (e.g. demyelination and axonal damage), and as such is playing an increasingly important role in monitoring experimental therapies for MS. One such application had been in the recently completed clinical trial of Fingolimod, which showed a clear reduction in the risk of developing a second attack and with marked reduction in the number of new lesions. Fingolimod is the lead molecule in a new class of drugs acting on the immune system by modulating the sphingosine-1-phosphate receptor (impeding lymphocyte migration into the central nervous system), and is the first oral treatment approved by the US Food and Drug Administration for MS. Considered as one of the top 10 innovations in medicine for 2011 (Cleveland Clinic). Recently completed clinical trials with Fingolimod indicate that this drug may be superior to interferon beta 1a in its ability to reduce inflammatory activity disability progression. MS is frequently accompanied by motor disability, which affects the most socially and work-active population (young adults). Voltagedependent potassium channels, present on the axonal membrane and exposed (activated) following demyelinating damage of MS, are thought to be involved in such neuromotor problems. Blocking these channels (e.g. with the recently approved drugs such as Fampridine - chemical name 4-aminopyridine) improves visual function and motor skills and relieves fatigue in patients with MS, and is most effective with the chronic progressive form of MS. Fampridine has recently been approved both in the U.S. and Europe. Three symposia were directed to Parkinson's disease (PD). PD is the most common chronic progressive neurodegenerative movement disorder, and is characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. There are about 250 cases of PD for every 100,000 inhabitants. The current therapeutic ‘kit’ for PD includes, apart from the traditional L-DOPA, direct dopamine agonists and inhibitors of monoamine oxidase and catechol-O-methyl transferase. Unfortunately these drugs with time loose their efficacy, and are unable to control disease symptoms in the advanced stages. Moreover, the non-motor symptoms of PD do not respond to current therapies. Electrostimulation has proven of utility in a very limited number of patients to date. Unlike previous surgeries for PD, deep brain stimulation (DBS) does not damage healthy brain tissue by destroying nerve cells. Instead the procedure blocks electrical signals from targeted areas in the brain. Thus, if newer, more promising treatments develop in the future, the DBS procedure can be reversed. Although most patients still need to take medication after undergoing DBS, many experience considerable reduction of their PD symptoms and are able to greatly reduce their medications. The reduction in dose of medication leads to a significant improvement in side effects such as dyskinesias. In some cases, the stimulation itself can suppress dyskinesias without a reduction in medication. In the U.S., the National Institute of Neurological Disorders and Stroke is currently supporting research on DBS to determine its safety, reliability, and effectiveness, and to determine the site(s) in the brain where DBS surgery will be most effective in reducing PD symptoms. New studies show that the utilization of sensory information and observing alterations in motor control and learning (e.g. by means of video clips) in patients with extrapyramidal disorders (PD, essential tremor, dystonia) can be used to improve walking capability. Neuroinflammation is an area of vigorous research within the neuroscience community, at both the clinical and preclinical levels. Appropriately, a symposium dealing with the pharmacological modulation of microglia in neurodegenerative pathologies and neuroinflammation was held. Chronic neuropathic (or neurogenic) pain differs from other types of pain because it is not caused by physical injury. Unlike inflammatory or nociceptive pain, neuropathic pain represents a maladaptive response to a lesion or dysfunction that directly involves the somato-sensory system and manifests itself as hyperalgesia, allodynia and spontaneous pain. While neuropathic pain can arise as a consequence of a noxious event in the periphery, e.g. at the tissue or endoneural level, it can also occur as a result of noxae that are: primarily spinal, generally of a traumatic or degenerative nature; supraspinal (central) noxae of a traumatic, dysmetabolic or degenerative nature. A good example of this is the neuropathic pain not infrequently experienced by MS patients. Interactions between the nervous (neurons) and immune (non-neuronal cells) systems are now viewed as representing a key element in pain, including neuropathic, as well as in neurodegenerative diseases. Mast cells resident in innervated tissues and the endoneural compartment, and microglia at the spinal and supraspinal level – together with their potential for crosstalk – constitute highly promising targets for therapeutic intervention. In the case of microglia, the processes which modify their phenotype and determine a neuroinflammatory and/or neuroprotective direction remain to be fully understood. Pharmacological approaches have included antibiotics like minocycline to inhibit microglia proliferation, drugs aimed to specific targets such as chemokine receptors (e.g. fractakine) and, better still, agents capable of shifting cellular phenotype to an antiinflammtory and neuroprotective ‘form’. The classical cannabinoids and so-called endocannabinoids, while efficacious, are often handicapped by issues of tolerability/side effects. There is a growing appreciation that endogenous endocannabinoid-like molecules, the fatty acid amides of ethanolamine and, in particular palmitoylethanolamide (PEA), are capable of a modulatory inhibition of spinal and supraspinal microglia and peripherally located mast cells. Interestingly, microglia can synthesize and degrade PEA, suggesting an autocrine/paracrine mode of action. However, in a disease setting endogenous mechanisms may be inadequate, in which case exogenous administration of PEA may provide an innovative therapeutic approach oriented to the moderation of neuroinflammatory phenomena connected with these non-neuronal cells, in both chronic pain states and degeneration.

Alzheimer's disease (AD) is the principal cause of dementia, which is characterized by gradual onset of and progression of deficits in cognition and memory. The neuropathological hallmarks of AD are β-amyloid (Aβ) deposition in senile plaques and neurofibrillary tangles composed of the protein tau in a hyperphosphorylated state. The amyloid cascade hypothesis, which posits that deposition of Aβ in the brain parenchyma initiates a sequence of events that ultimately lead to AD dementia, has dominated research for the past twenty years. Drug development efforts have focused on reducing production of Aβ or enhancing its clearance from the brain. However, all of the Aβ-centric approaches that reached Phase III clinical trials have failed. These therapeutics were designed to decrease Aβ production (e.g. β- and γ- secretase inhibitors, γ-secretase modulators), to inhibit aggregation and/or bust plaques to improve Aβ clearance, and to inactivate Aβ through immunotherapy by active vaccination against the peptide or passive immunization with anti-Aβ antibodies. However, only direct intracranial delivery of anti-Aβ antibody – a route of administration unlikely to be used in a clinical setting - has been definitively shown to clear preexisting deposits. In a new study reported in The Journal of Neuroscience, Wang and colleagues evaluated the possibility of combining multiple anti-Aβ therapies in the treatment of AD. The authors used tet-off amyloid precursor protein (APP) transgenic mice combined with anti-Aβ immunotherapy. Treatment of amyloid-bearing tet-off APP mice with doxycycline was performed to suppress transgenic Aβ production before initiating a 12-week course of passive immunization. This strategy led to the preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. Peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain and enhanced microglial internalization of aggregated Aβ. To demonstrate the effectiveness of their approach in aged (18-24 month) animals, the authors suppressed transgenic APP until the mice reached 12 months of age, thus generating 18-month-old mice that carried only 6 months of amyloid load (thereby avoiding severe plaque burden before mid-life.). Combination therapy was equally effective in aged animals and in young (6-12 month) adults. Repeated injections with anti-Aβ antibodies can increase vascular amyloid and microhemorrhage. However, the frequency of microhemorrhage but not the severity of individual bleeds was significantly increased by antibody treatment in the study by Wang et al. In addition, the authors did not directly test the effect of Aβ antibody alone in their tet-off APP mice. However, in an earlier study from this lab passive immunization using the same antibody found only modest attenuation of amyloid loads in APP transgenic mice that started antibody treatment with much less amyloid than the tet-off APP mice. These caveats notwithstanding, the findings highlight a therapeutic potential for arresting the production of Aβ, with a combination therapy that allows microglial clearance to work from a static amyloid burden towards a significant reduction in plaque load. To paraphrase the authors: “draining a flood is easier once the water stops’.

Recent developments in nanoparticle research have resulted in new opportunities to target drug delivery to the central nervous system (CNS) for treating various brain diseases [1-3]. Nanoparticle-based drug delivery is generally considered to be innocuous in reaching the CNS targets across the blood-brain barrier (BBB) without damaging it [3, 4]. However, new data emerging in the field suggests that neurotoxicity of nanoparticles must be considered in detail before suitable therapeutic strategies are developed to treat patients using nanomedicine [4]. Thus, the need of the hour is to understand the possible effects of nanoparticles on neurotoxicity in vivo. Few reports in cell culture suggest that several nanoparticles, depending on their size, may induce neurotoxicity [3, 4]. Sporadic in vivo findings show that nanoparticles induce cell and tissue damage in the respiratory system following inhalation in animal models [cf 1, 5]. This damage is inversely proportional to the size of the nanoparticles [5]. However, systematic studies in vivo on neurotoxicity of nanoparticles in the CNS are still lacking. Likewise, drug delivery to the CNS is normally accomplished utilizing different kinds of liposomes or related techniques. Recent development of nanowires from different metals that could potentially trap several drug molecules and release them in vivo when implanted has come up [1, 2]. However, the potential role of nanowired delivery of drugs in the CNS is still not well investigated [5, 6]. Thus, there is an urgent need to understand the role of nanowired drug delivery in relation to the toxicity of the nanowire alone, if any, in the CNS using an in vivo model [6-9]. To further expand these new ideas systematic studies on nanoparticle-induced neurotoxicity in specific CNS regions is highly needed. In addition, it is still unclear whether nanoparticle exposure of healthy individuals or persons with common diseases e.g., hypertension or diabetes will modify brain dysfunction [1, 5]. Furthermore, traumatic injuries to the CNS following nanoparticle intoxication may have dangerous consequences that require adjustment of drug dose [cf 1, 6-8]. These are important questions for policy makers, educators and health service providers that require further investigation. Keeping these new developments in Nanoneuroscience in mind during the past 5 years, there is a need to summarize the current state of the art in the field. This special issue of CNS & Neurological Disorders - Drug Targets focuses on “Nanoneuroprotection and Nanoneurotoxicity”, two faces of the same coin, as addressed by leading world experts. The volume is a referred collection of Invited Reviews by World leaders on Nanoneuroscience and related disciplines comprising neurosurgeons, neurophysiologists, neurpathologists, neurophramacologists and neurologists. The salient new features of this volume includes a commentary by Russell J Andrews (Moffet Field, CA, USA) on novel aspects of nano drug delivery. Dafin F Muresanu (Cluj- Napoca, Romania) and co-workers discussed TiO2 nanowired delivery of antioxidants to treat successfully hyperthermia-induced brain damage. Jose V Lafuente (Bilbao, Spain) and his team present new evidence showing that diabetes-induced brain pathology is aggravated by chronic SiO2 exposure. Neurotoxicity of metal nanoparticles is presented by Hari S Sharma (Uppsala, Sweden) who shows that species differences could play an important part in nanoparticle-induced neurotoxicity. To treat nanoparticle-induced neurotoxicity new drug treatments are needed. In this regard, Aruna Sharma (Uppsala University) shows that cerebrolysin is having superior neuroprotective effects in heat stroke after nanoparticle intoxication, as compared to other drugs in identical doses. Furthermore, a double dose of cerebrolysin is needed to induce marked neuroprotection in hyperthermia after nanoparticle exposure. Nanodrug delivery of metal chelators is able to reduce Alzheimer's disease-induced pathology. This is shown by Mark A Smith (Cleveland, Ohio, USA) and his team clearly. In this context Ryan Z Tian (Fayetteville, AR, USA) and co-workers provide new evidence that nanowired drug delivery using TiO2 nanowires in spinal cord injury is more neuroprotective than the parent compound. However, different compounds used may have different neuroprotective ability. This suggests that nanowired delivery of drugs could enhance their therapeutic efficacy but could not transform a non-performing drug into a neuroprotective agent. Lastly, Preeti Menon (Uppsala, Sweden) and co-workers show that cerebrolysin not only provides neuroprotection in hyperthermia-induced brain pathology following nanoparticle intoxication, but also is quite suitable to induce efficient neuroprotection following spinal cord injury after nanoparticle intoxication. These eight selected reviews focus on key factors of nanopartiocle-induced neurotoxicity and neuroprotection. We believe that new strategies discussed here will open new avenues for research in CNS injury that could lead to exploration of novel drug targets and therapeutic agents. This volume is indispensable for neurophramacologists, neurotoxicologists, nanotechnologists, neuroimmunologists, neurosurgeons, military experts, policy makers, educators and students alike. We sincerely hope that data presented in this volume will stimulate further research in Nanomedicine.

In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world’s population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed.

Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations.

Spinal cord injury (SCI) is the world’s most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins and the number of injured neurons. This indicates that cerebrolysin in higher doses could be a good candidate for treating SCI cases following nanoparticle intoxication. The possible mechanisms and functional significance of these findings are discussed in this review.

Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle-intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by nanowired drug delivery is discussed that is largely based on our own investigations.

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.

The pathological lesions typical of Alzheimer disease (AD) are sites of significant and abnormal metal accumulation. Metal chelation therapy, therefore, provides a very attractive therapeutic measure for the neuronal deterioration of AD, though its institution suffers fundamental deficiencies. Namely, chelating agents, which bind to and remove excess transition metals from the body, must penetrate the blood-brain barrier to instill any real effect on the oxidative damages caused by the presence of the metals in the brain. Despite many advances in chelation administration, however, this vital requirement remains therapeutically out of reach: the most effective chelators-i.e., those that have high affinity and specificity for transition metals like iron and copper-are bulky and hydrophilic, making it difficult to reach their physiological place of action. Moreover, small, lipophilic chelators, which can pass through the brain’s defensive wall, essentially suffer from their over-effectiveness. That is, they induce toxicity on proliferating cells by removing transition metals from vital RNA enzymes. Fortunately, research has provided a loophole. Nanoparticles, tiny, artificial or natural organic polymers, are capable of transporting metal chelating agents across the blood-brain barrier regardless of their size and hydrophilicity. The compounds can thereby sufficiently ameliorate the oxidative toxicity of excess metals in an AD brain without inducing any such toxicity themselves. We here discuss the current status of nanoparticle delivery systems as they relate to AD chelation therapy and elaborate on their mechanism of action. An exciting future for AD treatment lies ahead.

Spinal cord injury (SCI) is a serious clinical situation for which no suitable drug therapy exists. SCI often results in paraplegia or quadriplegia and, apart from the personal trauma leads to huge costs to society for rehabilitation or day-to-day life support. Sensory motor dysfunction following SCI is mainly a consequence of the slowly progressing cord pathology after primary injury that worsens over tine. Thus, almost all sensory and motor nerve control and pathways passing through spinal cord and reflexes are compromised in SCI patients. As a result their peripheral nervous system, autonomic nervous function and central nervous system regulations are adversely affected. Experiments carried out in our laboratory show that various therapeutic agents, if given within 10 to 30 minutes after primary SCI could correct morphological changes to a certain extent. In these rat models of SCI reduction in cord pathology, e.g., bloodspinal cord barrier (BSCB) breakdown, edema formation and cell injury by the neuroprotective agents that also limited sensory motor dysfunction and improved functional behavior. However, these drugs if given beyond 30 minutes after SCI showed a markedly reduced neuroprotective efficacy. Thus, new strategies are needed to enhance neuroprotection in SCI to prevent structural and functional changes over longer periods of time. To that end our laboratory has initiated a series of investigations in which nanowired delivery of various neurotherapeutic agents are applied after different time periods of SCI, that resulted in a much better outcome than with the parent compounds under identical conditions. The superior neuroprotective activity of nanowired compound delivery could be due to a reduced metabolism of active compounds in the central nervous system (CNS) or by sustained release of the drug for longer times. In addition, nanowired drugs may penetrate the CNS faster and could reach widespread areas once entering the spinal cord. Thus, nanowired drug delivery to treat SCI may have potential therapeutic value. These aspects of nanowired drug delivery to enhance neuroprotection in SCI are discussed in this review based on our own investigations.

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