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.
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.
Nanoparticles are small sized (1–100 nm) particles derived from transition metals, silver, copper, aluminum, silicon, carbon and metal oxides that can easily cross the blood–brain barrier (BBB) ...and/or produce damage to the barrier integrity by altering endothelial cell membrane permeability. However, the influence of nanoparticles on BBB integrity is still not well-known. In this investigation, effect of nanoparticles derived from Ag, Al and Cu (50–60 nm) on BBB permeability in relation to brain edema formation was examined in a rat model. Intravenous (30 mg/kg), intraperitoneal (50 mg/kg) or intracerebral (20 µg in 10 µL) administration of Ag, Cu or Al nanoparticles disrupted the BBB function to Evans blue albumin (EBA) and radioiodine in rats 24 h after administration and induced brain edema formation. The leakage of Evans blue dye was observed largely in the ventral surface of brain and in the proximal frontal cortex. The dorsal surfaces of cerebellum showed mild to moderate EBA staining. These effects were most pronounced in animals that received Ag or Cu nanoparticles compared to Al nanoparticles through intravenous routes. These observations are the first to suggest that nanoparticles can induce brain edema formation by influencing BBB breakdown in vivo.
Influence of nanoparticles on brain function following in vivo exposures is not well known. Depending on the magnitude and intensity of nanoparticle exposure from the environment, food and/or water ...source, neuronal function could be affected and may lead to neurotoxicity and neuropathology. This hypothesis was examined in present investigation using systemic or intracerebroventricular administration of engineered nanoparticles from metals, i.e., Al, Ag and Cu (approximately equal to 50 to 60 nm) on neurotoxicity in rats and mice. Intraperitoneal (50 mg/kg), intravenous (30 mg/kg), intracarotid (2.5 mg/kg) or intracerebroventricular administration (20 microg) of nanoparticles significantly altered the blood-brain barrier (BBB) function to Evans blue and radioiodine in several regions of the brain and spinal cord at 24 h after their administration. Marked decreases in local cerebral blood flow (CBF) and pronounced brain edema was seen in regional areas associated with BBB leakage. Neuronal cell injuries, glial cell activation, heat shock protein (HSP) upregulation and loss of myelinated fibers are quite common in effected brain areas. The observed pathological changes were most pronounced in mice compared to rats. Exposures to Cu and Ag nanoparticles showed most marked effects on brain pathology when administered into systemic circulation or into the brain ventricular spaces as compared to Al nanoparticles. Our results are the first to show that nanoparticles from metals are able to induce selective and specific neurotoxicity that depends on the type of metals, route of administration and the species used.
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.
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.
The possibility that diabetes aggravates nanoparticles induced blood-brain barrier (BBB) breakdown, edema formation and brain pathology was examined in a rat model. Engineered nanoparticles from ...metals Ag and Cu (50-60 mn) were administered (50 mg/kg, i.p.) once daily for 7 days in normal and streptozotocine induced diabetic rats. On the 8th day, BBB permeability to Evans blue and radioactive iodine (131I-sodium) was examined in 16 brain regions. In these brain regions alterations in regional CBF was also evaluated using radiolabelled (125I) carbonized microspheres (o.d. 15 +/- 6 microm). Regional brain edema and Na+, K+ and Cl- ion analysis were done in 8 selected brain regions. Histopathology was used to detect neuronal damage employing Nissl staining. Nanoparticles treatment in diabetic rats showed much more profound disruption of the BBB to Evans blue albumin (EBA) and radioiodine in almost all the 16 regions examined as compared to the normal animals. In these diabetic animals reduction in regional cerebral blood flow (CBF) was more pronounced than in normal rats. Edema development as seen using water content and increase in Na+ and a decrease in K+ ion were most marked in diabetic rats as compared to normal rats after nanoparticles treatment. Cell changes in the regions of BBB disruptions were also exacerbated in diabetic rats compared to normal group after nanoparticles treatment. Taken together, these observations are the first to show that diabetic rats are more susceptible to nanoparticles induced cerebrovascular reactions in the brain and neuronal damage. The possible mechanisms and significance of the present findings are discussed.
Transient global ischemic cerebral injury is a consequence of cardiac arrest and accounts for approximately 450,000 annual deaths with a mortality of approximately 90%. Serious morbidity follows for ...many of the survivors and up to 16% of patients achieving restoration of spontaneous circulation develop brain death. Other survivors are left with persistent cognitive impairment such as memory and sensimotor deficits, reducing quality of life and resulting in heavy costs on society. Many studies over the years have been devoted to improving outcome after cardiac arrest and have, to a certain degree succeeded, especially locally in areas where improvement of ambulance organizations have been effective. In spite of this serious problems remain and the chances of cerebral survival need to increase if over-all results, i.e. survival as well as cognitive function, are to improve. Methylene blue, a textile dye synthesized in the late 19th century has also been used in medicine for different purposes. One of its effects is to increase systemic blood pressure, but other effects have been documented, among which are its neuroprotective effects well-noted during the last few years. In this review we have appraised these findings in relation to global ischemic injury.
The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults ...BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.
