Blood-Brain Barrier Changes in High Altitude Lafuente, José V; Bermudez, Garazi; Camargo-Arce, Lorena ...
CNS & neurological disorders drug targets,
01/2016, Letnik:
15, Številka:
9
Journal Article
Recenzirano
Cerebral syndromes related to high-altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed ...by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB considered to play an important role. A fuller comprehension of these processes is crucial to reduce and prevent BBB alterations during high-altitude exposure.
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 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.
Exposure to an enriched environment (EE) has neuroprotective benefits and improves recovery from brain injury due to, among other, increased neurotrophic factor expression. Through these ...neurotrophins, important cortical and hippocampal changes occur. Vandetanib acts as a tyrosine kinase inhibitor of cell receptors, among others, the vascular endothelial growth factor receptor (VEGFR). Our aim was to investigate the effectiveness of EE counteracting cognitive and cellular effects after tyrosine kinase receptor blockade. Animals were reared under standard laboratory condition or EE; both groups received vandetanib or vehicle. Visuospatial learning was tested with Morris water maze. Neuronal, interneuronal, and vascular densities were measured by inmunohistochemistry and histochemistry techniques. Quantifications were performed in the hippocampus and in the visual cortex. Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), Akt, and Erk were measured by Western blot technique. Vandetanib produces a significant decrease in vascular and neuronal densities and reduction in the expression of molecules involved in survival and proliferation processes such as phospho-Akt/Akt and phospho-Erk/Erk. These results correlated to a cognitive impairment in visuospatial test. On the other hand, animals reared in an EE are able to reverse the negative effects, activating PI3K-AKT and MAP kinase pathways mediated by BDNF-TrkB binding. Present results provide novel and consistent evidences about the usefulness of living in EE as a strategy to improve deleterious effects of blocking neurotrophic pathways by vandetanib and the notable role of the BDNF-TrkB pathway to balance the neurovascular unit and cognitive effects.
Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs ...exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO
2
-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10–11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.
We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38°C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell ...injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4-to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x10(6)) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future.
Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that ...acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT
3
receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.
The development of the cortical vascular network depends on functional maturation. External inputs are an essential requirement in the modeling of the visual cortex, mainly during the critical ...period, when the functional and structural properties of visual cortical neurons are particularly susceptible to alterations. Vascular endothelial growth factor (VEGF) is the major angiogenic factor, a key signal in the induction of vessel growth. Our study focused on the role of visual stimuli on the development of the vascular pattern correlated with VEGF levels. Vascular density and the expression of VEGF were examined in the primary visual cortex of rats reared under different visual environments (dark rearing, dark-rearing in conditions of enriched environment, enriched environment, and laboratory standard conditions) during postnatal development (before, during, and after the critical period). Our results show a restricted VEGF cellular expression to astroglial cells. Quantitative differences appeared during the critical period: higher vascular density and VEGF protein levels were found in the enriched environment group; both dark-reared groups showed lower vascular density and VEGF levels, which means that enriched environment without the physical exercise component does not exert effects in dark-reared rats.
Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce ...Parkinson’s disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased α-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.
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, TiO
-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.
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