Asya Ozkizilcik

Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair

The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

Synthesis of Biocompatible Titanate Nanofibers for Effective Delivery of Neuroprotective Agents

Nanoscience provides us with new opportunities to develop nanotechnologies for treating, in particular, central nervous system disorders such as Alzheimer disease and multiple sclerosis. From a methodological point of view, it is challenging to deliver drugs effectively across the blood-brain barrier and blood-cerebrospinal fluid barrier. Our 10-year data and reports from both in vivo and in vitro studies, however, have consistently proved that therapeutic drugs of different types can be generally loaded in/on the nanocarriers for targeted and programmable deliveries to the central nervous system with a high degree of efficacy. This chapter presents a protocol for the synthesis of biocompatible titanate nanofibers as low-cost drug delivery cargos. In addition, a procedure for loading the neuroprotective agent Cerebrolysin onto the nanofibers is briefly described. Finally, experimental observations on the use of nanodrug delivery for superior neuroprotective effects of Cerebrolysin in traumatic brain injury are given as a proof of concept as compared to normal drug alone.

Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology: New Roles of Nanowired Drug Delivery for Neuroprotection

The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.

Sleep Deprivation Induced Blood-Brain Barrier Breakdown and Brain Pathology. Neuroprotective Effects of TiO 2 -Nanowired Delivery of Cerebrolysin and Ondansetron

Military personnel are often subjected to sleep deprivation (SD) for long hours during combat or peacekeeping operations across the Globe. Recent reports suggests that sound sleep for less than 4 h results in confusion, simple task calculations, and affects decision making. However, in military life SD of 12–72 h is quite common. It appears that longer duration of SD is related to brain dysfunction. Model experiments carried out in our laboratory show that 12–72 h of SD in rats results in progressive breakdown of the blood-brain barrier (BBB) to proteins and induce brain edema formation. Selective neuronal, glial cell and axonal injuries also occurred in SD that is progressive in nature. Interestingly, the magnitude and intensity of SD depends on environmental temperature and cardiovascular health of the animals. Thus, SD at 34 °C induces 2- to 4- fold brain damage, BBB breakdown and edema formation in rats as compared to identical SD at room temperature (21 ± 1 °C). Also hypertensive rats when subjected to identical SD showed greater degree of brain pathology as compared to normotensive animals. Treatment with a multimodal drug Cerebrolysin that is a balanced composition of several neurotrophic factors and active peptide fragments significantly reduced the brain pathology in healthy animals at room temperature. However, TiO2-nanowired delivery of cerebrolysin is needed to attenuate SD induced brain pathology of normotensive rats at hot environment or hypertensive animals at room temperature. These observations suggest that nanodrug delivery in SD is needed to induce neuroprotection at hot environment or in hypertensive animals, not reported earlier.

Nanocarriers as CNS Drug Delivery Systems for Enhanced Neuroprotection

Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BSCFB) separate central nervous system (CNS) from blood circulation and tightly protect CNS by hindering the passage of harmful substances across the barriers and allowing the transport of essential compounds for brain function. These selectively permeable barriers have become a major challenge in delivering drugs into the nervous system for the treatment of CNS diseases and complications such as Alzheimer’s disease, Multiple sclerosis, and encephalitis. Due to the advancements in nanotechnology and medicine, nanocarrier-based drug delivery has emerged as a new and potential strategy for neurological treatment and protection. Depending on the techniques in preparation and functionalization, nanocarriers may be developed with different properties for cell-/tissue-/organ-specific targeted delivery and for sustained and controlled release of neurotherapeutic agents. Even though several attempts have shown successful results in effective drug delivery to the central nervous system, the lack of information about long-term nanocarrier toxicity, accumulation, and excretion restrict their use in current clinical practice. This chapter highlights recent developments in nanocarriers specifically designed to protect CNS. The interactions between nanocarriers including liposomes, micelles, organic and inorganic nanoparticles, nanofibers, and carbon-based materials with various neuroprotective agents, and their capabilities of delivering the encapsulated or conjugated drugs to the CNS are reviewed. The review also includes our investigations on the development of titanate nanospheres and nanowires and their potential use as drug delivery tools in neuroprotection. Finally, future prospects of drug delivery systems in the treatment of neurodegenerative pathologies for clinical translation are described.

Spinal Cord Injury at Hot Environment Exacerbates Blood-spinal Cord Barrier Disruption, Edema Formation and Cellular Damages. Effective Treatment With a Multimodal Drug Cerebrolsyi

Introduction/Rational: Military personnel engaged in combat operation are often exposed to desert storm resulting in silica dust (SiO2 nanoparticles) intoxication. In addition, combat stress, sleep ...Introduction/Rational: Military personnel are highly vulnerable to concussive head injury (CHI) during combat operations resulting in long-term disability. Since no suitable treatments are availabl ...Introduction/Rational: Traumatic injuries to the central nervous system (CNS) occurring at cold or hot environments may affect the pathological outcome. In addition, this is not known whether injur ...For those of you unable to attend the NABIS meeting, we hope that the abstracts presented in the following pages will at least give you a feel for our annual event. In addition the nearly 100 oral and poster presentations abstracted in this issue, over 40 invited speakers will present the latest advances in the science, rehabilitation and treatment of traumatic brain injury. The preliminary conference program is posted on the NABIS website, www.nabis.org.

Novel Treatment Strategies Using TiO 2 -Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease

More than 5.5 million Americans of all ages are suffering from Alzheimers disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AβP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AβP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.

Need to Explore Nanodelivery of Stem Cells with Multimodal Drug like Cerebrolysin for Effective Strategies for Enhanced Neuroprotection and Neurorecovery in Neurodegenerative Disorders

Central nervous system (CNS) is vulnerable to various kinds of physical, chemical, metabolic or age-related insults leading to neurodegeneration. Neurodegenerative diseases either caused by aging or following trauma to the CNS results in misery for large number of people across the Globe involving high social costs for them to maintain a good life [1].