Browsing by Author "Lars Wiklund"

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Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide
(Elsevier B.V., 2021) Hari Shanker Sharma; Dafin F. Muresanu; Rudy J. Castellani; Ala Nozari; José Vicente Lafuente; Anca D. Buzoianu; Seaab Sahib; Z. Ryan Tian; Igor Bryukhovetskiy; Igor Manzhulo; Preeti K. Menon; Ranjana Patnaik; Lars Wiklund; Aruna Sharma
Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin—a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier. © 2021 Elsevier B.V.
Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome
(Academic Press Inc., 2019) Hari Shanker Sharma; Dafin Fior Muresanu; Ala Nozari; Rudy J. Castellani; Prasanta Kumar Dey; Lars Wiklund; Aruna Sharma
Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224 N on the right parietal bone by dropping a weight of 114.6 g from a 20 cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35 mg/kg, i.p.), pentobarbital (50 mg/kg, i.p.), equithesin (3 mL/kg, i.p.) and urethane (1 g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory. © 2019 Elsevier Inc.
Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology. Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy
(Elsevier B.V., 2021) Aruna Sharma; Dafin F. Muresanu; Ranjana Patnaik; Preeti K. Menon; Z. Ryan Tian; Seaab Sahib; Rudy J. Castellani; Ala Nozari; José Vicente Lafuente; Anca D. Buzoianu; Stephen D. Skaper; Igor Bryukhovetskiy; Igor Manzhulo; Lars Wiklund; Hari Shanker Sharma
Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25 μL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier. © 2021 Elsevier B.V.
Methamphetamine exacerbates pathophysiology of traumatic brain injury at high altitude. Neuroprotective effects of nanodelivery of a potent antioxidant compound H-290/51
(Elsevier B.V., 2021) Hari Shanker Sharma; José Vicente Lafuente; Lianyuan Feng; Dafin F. Muresanu; Preeti K. Menon; Rudy J. Castellani; Ala Nozari; Seaab Sahib; Z. Ryan Tian; Anca D. Buzoianu; Per-Ove Sjöquist; Ranjana Patnaik; Lars Wiklund; Aruna Sharma
Military personnel are often exposed to high altitude (HA, ca. 4500–5000 m) for combat operations associated with neurological dysfunctions. HA is a severe stressful situation and people frequently use methamphetamine (METH) or other psychostimulants to cope stress. Since military personnel are prone to different kinds of traumatic brain injury (TBI), in this review we discuss possible effects of METH on concussive head injury (CHI) at HA based on our own observations. METH exposure at HA exacerbates pathophysiology of CHI as compared to normobaric laboratory environment comparable to sea level. Increased blood-brain barrier (BBB) breakdown, edema formation and reductions in the cerebral blood flow (CBF) following CHI were exacerbated by METH intoxication at HA. Damage to cerebral microvasculature and expression of beta catenin was also exacerbated following CHI in METH treated group at HA. TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant significantly enhanced CBF and reduced BBB breakdown, edema formation, beta catenin expression and brain pathology in METH exposed rats after CHI at HA. These observations are the first to point out that METH exposure in CHI exacerbated brain pathology at HA and this appears to be related with greater production of oxidative stress induced brain pathology, not reported earlier. © 2021 Elsevier B.V.
Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury
(Elsevier B.V., 2021) Feng Niu; Aruna Sharma; Zhenguo Wang; Lianyuan Feng; Dafin F. Muresanu; Seaab Sahib; Z. Ryan Tian; José Vicente Lafuente; Anca D. Buzoianu; Rudy J. Castellani; Ala Nozari; Preeti K. Menon; Ranjana Patnaik; Lars Wiklund; Hari Shanker Sharma
Military personnel are the most susceptible to concussive head injury (CHI) caused by explosion, blast or missile or blunt head trauma. Mild to moderate CHI could induce lifetime functional and cognitive disturbances causing significant decrease in quality of life. Severe CHI leads to instant death and lifetime paralysis. Thus, further exploration of novel therapeutic agents or new features of known pharmacological agents are needed to enhance quality of life of CHI victims. Previous reports from our laboratory showed that mild CHI induced by weight drop technique causing an impact of 0.224 N results in profound progressive functional deficit, memory impairment and brain pathology from 5 h after trauma that continued over several weeks of injury. In this investigation we report that TiO2 nanowired delivery of oxiracetam (50 mg/kg, i.p.) daily for 5 days after CHI resulted in significant improvement of functional deficit on the 8th day. This was observed using Rota Rod treadmill, memory improvement assessed by the time spent in finding hidden platform under water. The motor function improvement is seen in oxiracetam treated CHI group by placing forepaw on an inclined mesh walking and foot print analysis for stride length and distance between hind feet. TiO2-nanowired oxiracetam also induced marked improvements in the cerebral blood flow, reduction in the BBB breakdown and edema formation as well as neuroprotection of neuronal, glial and myelin damages caused by CHI at light and electron microscopy on the 7th day after 5 days TiO2 oxiracetam treatment. Adverse biochemical events such as upregulation of CSF nitrite and nitrate, IL-6, TNF-a and p-Tau are also reduced significantly in oxiracetam treated CHI group. On the other hand post treatment of 100 mg/kg dose of normal oxiracetam in identical conditions after CHI is needed to show slight but significant neuroprotection together with mild recovery of memory function and functional deficits on the 8th day. These observations are the first to point out that nanowired delivery of oxiracetam has superior neuroprotective ability in CHI. These results indicate a promising clinical future of TiO2 oxiracetam in treating CHI patients for better quality of life and neurorehabilitation, not reported earlier. © 2021 Elsevier B.V.
Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke
(Elsevier B.V., 2021) Seaab Sahib; Aruna Sharma; Dafin F. Muresanu; Zhiqiang Zhang; Cong Li; Z. Ryan Tian; Anca D. Buzoianu; José Vicente Lafuente; Rudy J. Castellani; Ala Nozari; Ranjana Patnaik; Preeti K. Menon; Lars Wiklund; Hari Shanker Sharma
Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed. © 2021 Elsevier B.V.
Neuroprotective effects of insulin like growth factor-1 on engineered metal nanoparticles Ag, Cu and Al induced blood-brain barrier breakdown, edema formation, oxidative stress, upregulation of neuronal nitric oxide synthase and brain pathology
(Elsevier B.V., 2021) Hari Shanker Sharma; José Vicente Lafuente; Dafin F. Muresanu; Seaab Sahib; Z. Ryan Tian; Preeti K. Menon; Rudy J. Castellani; Ala Nozari; Anca D. Buzoianu; Per-Ove Sjöquist; Ranjana Patnaik; Lars Wiklund; Aruna Sharma
Military personnel are vulnerable to environmental or industrial exposure of engineered nanoparticles (NPs) from metals. Long-term exposure of NPs from various sources affect sensory-motor or cognitive brain functions. Thus, a possibility exists that chronic exposure of NPs affect blood-brain barrier (BBB) breakdown and brain pathology by inducing oxidative stress and/or nitric oxide production. This hypothesis was examined in the rat intoxicated with Ag, Cu or Al (50–60 nm) nanoparticles (50 mg/kg, i.p. once daily) for 7 days. In these NPs treated rats the BBB permeability, brain edema, neuronal nitric oxide synthase (nNOS) immunoreactivity and brain oxidants levels, e.g., myeloperoxidase (MP), malondialdehyde (MD) and glutathione (GT) was examined on the 8th day. Cu and Ag but not Al nanoparticles increased the MP and MD levels by twofold in the brain although, GT showed 50% decline. At this time increase in brain water content and BBB breakdown to protein tracers were seen in areas exhibiting nNOS positive neurons and cell injuries. Pretreatment with insulin like growth factor-1 (IGF-1) in high doses (1 μg/kg, i.v. but not 0.5 μg/kg daily for 7 days) together with NPs significantly reduced the oxidative stress, nNOS upregulation, BBB breakdown, edema formation and cell injuries. These novel observations demonstrate that (i) NPs depending on their metal constituent (Cu, Ag but not Al) induce oxidative stress and nNOS expression leading to BBB disruption, brain edema and cell damage, and (ii) IGF-1 depending on doses exerts powerful neuroprotection against nanoneurotoxicity, not reported earlier. © 2021 Elsevier B.V.
Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: An experimental study in the rat
(New York Academy of Sciences, 2005) Hari Shanker Sharma; Rajendra D. Badgaiyan; Per Alm; S. Mohanty; Lars Wiklund
The role of nitric oxide (NO) in spinal cord injary (SCI)-indnced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-indaced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology. © 2005 New York Academy of Sciences.
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: Part 1(Patient Dynamics): Preoperative demographics and preoperative and operative risk factors
(BioMed Central Ltd, 2021) W. R. Eric Jamieson; John L. Ely; Johan Brink; Timothy Pennel; Paul Bannon; Jashvant Patel; Rajiv Kumar Gupta; Prasanna Simha Mohan Rao; Damyanti Agrawal; Lars Wiklund; A. Pieter Kappetein; Rune Haaverstad; Thomas Geisner; Torsten Doenst; Christian Schlensak; Salgunan Nair; Craig Brown; Matthias Siepe; Ralph J. Damiano; Yves Langlois; K.M. Cherian; Hormoz Azar; John C. Chen; Joseph E. Bavaria; Lynn M. Fedoruk; Nabil A. Munfakh; V. Sridhar; Peter M. Scholz; Thomas A. Pfeffer; Jian Ye
Objectives: The PROSE trial purpose is to investigate whether the incidence of thromboembolic—related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc.—On-X) compared with a previous generation mechanical prosthesis (St Jude Medical—SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. Methods: The PROSE study was conducted in 28 worldwide centres and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors. Results: The total patient population (855) incorporated On-X population (462) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic and mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. Conclusions: The preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations. © 2021, The Author(s).
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: Part 2: Study results—prostheses, positions, and economic development
(Elsevier B.V., 2022) W. R. Eric Jamieson; John L. Ely; Johan Brink; Timothy Pennel; Paul Bannon; Jashvant Patel; Rajiv Kumar Gupta; Prasanna Simha Mohan Rao; Damyanti Agrawal; Lars Wiklund; A. Pieter Kappetein; Rune Haaverstad; Thomas Geisner; Torsten Doenst; Christian Schlensak; Salgunan Nair; Craig Brown; Matthias Siepe; Ralph J. Damiano; Yves Langlois; Kotturathu M. Cherian; Hormoz Azar; John C. Chen; Joseph E. Bavaria; Lynn M. Fedoruk; Nabil A. Munfakh; V. Sridhar; Peter M. Scholz; Thomas A. Pfeffer; Jian Ye
Objectives: The Prospective Randomized On-X Mechanical Prosthesis Versus St Jude Medical Mechanical Prosthesis Evaluation (PROSE) trial purpose was to investigate whether a current-generation mechanical prosthesis (On-X; On-X Life Technologies/Artivion Inc) reduced the incidence of thromboembolic-related complications compared with a previous-generation mechanical prosthesis (St Jude Medical Mechanical Prosthesis; Abbott/St Jude Medical). This second report documents the valve-related complications by individual prostheses and by Western and Developing populations. Methods: The PROSE trial study was conducted in 28 worldwide centers and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The study protocol, and analyses of 10 demographic variables and 24 risk factors were published in detail in 2021. Results: The total patient population (N = 855) included patients receiving an On-X valve (n = 462) and a St Jude Medical valve (n = 393). The overall freedom evaluation showed no differences at 5 years between the prostheses for thromboembolism or for valve thrombosis. There were also no differences in mortality. There were several differences between Developing and Western populations. The freedom relations at 5 years for mortality favored Western over Developing populations. Valve thrombosis was differentiated by position and site: aortic < mitral (P = .007) and Western < Developing (P = .005). In the mitral position there were no cases in Western populations, whereas there were 8 in Developing populations (P = .217). Conclusions: The On-X valve and St Jude Medical valve performed equally well in the study with no differences found. The only differentiation occurred with valve thrombosis in the mitral position more than the aortic position and occurring in Developing more than Western populations. The occurrence of valve thrombosis was also related to a younger population possibly due to anticoagulation compliance based on record review. © 2022 The Author(s)
Retraction note: Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood–Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain (Molecular Neurobiology, (2015), 52, 2, (1043-1053), 10.1007/s12035-015-9254-7)
(Springer, 2024) Hari S. Sharma; Ranjana Patnaik; Aruna Sharma; José Vicente Lafuente; Adriana Miclescu; Lars Wiklund
The Editor-in-Chief has retracted this article because of concerns regarding the figures presented in this work. These concerns call into question the article's overall scientific soundness. An investigation conducted after its publication discovered the following issues: The right half of the ROSC 120 min. Panel in Figure 1, when re-scaled, appears to overlap with the left half of the MB + ROSC 120 min. Panel in the same figure. These Panels represent tissues taken from animals subject to different experimental conditions; The right half of the MB + ROSC 120 min. Panel of Figure 1, when re-scaled, appears to overlap with the left half of the MB + ROSC 180 min. Panel in the same figure. These Panels represent tissues taken from animals subject to different experimental conditions. The right half of the ROSC 120 min. Panel in Figure 1, when re-scaled, appears to overlap with the left half of the MB + ROSC 120 min. Panel in the same figure. These Panels represent tissues taken from animals subject to different experimental conditions; The right half of the MB + ROSC 120 min. Panel of Figure 1, when re-scaled, appears to overlap with the left half of the MB + ROSC 180 min. Panel in the same figure. These Panels represent tissues taken from animals subject to different experimental conditions. The Editor-in-Chief therefore no longer has confidence in the integrity of the research presented in this article. Hari S. Sharma and Aruna Sharma disagree with this retraction. Ranjana Patnaik, José Vicente Lafuente, Adriana Miclescu, and Lars Wiklund have not replied to correspondence from the Publisher. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Superior antioxidant and anti-ischemic neuroprotective effects of cerebrolysin in heat stroke following intoxication of engineered metal Ag and Cu nanoparticles: A comparative biochemical and physiological study with other stroke therapies
(Elsevier B.V., 2021) Hari Shanker Sharma; Dafin F. Muresanu; Asya Ozkizilcik; Seaab Sahib; Z. Ryan Tian; José Vicente Lafuente; Rudy J. Castellani; Ala Nozari; Lianyuan Feng; Anca D. Buzoianu; Preeti K. Menon; Ranjana Patnaik; Lars Wiklund; Aruna Sharma
Military personnel are often exposed to high environmental heat associated with industrial or ambient abundance of nanoparticles (NPs) affecting brain function. We have shown that engineered metal NPs Ag and Cu exacerbate hyperthermia induced brain pathology. Thus, exploration of novel drug therapy is needed for effective neuroprotection in heat stroke intoxicated with NPs. In this investigation neuroprotective effects of cerebrolysin, a balanced composition of several neurotrophic factors and active peptides fragments exhibiting powerful antioxidant and anti-ischemic effects was examined in heat stroke after NPs intoxication. In addition, its efficacy is compared to currently used drugs in post-stroke therapies in clinics. Thus, levertiracetam, pregabalin, topiramat and valproate were compared in standard doses with cerebrolysin in heat stroke intoxicated with Cu or Ag NPs (50–60 nm, 50 mg/kg, i.p./day for 7 days). Rats were subjected to 4 h heat stress (HS) in a biological oxygen demand incubator at 38 °C (Relative Humidity 45–47%; Wind velocity 22.4–25.6 cm/s) that resulted in profound increase in oxidants Luminol, Lucigenin, Malondialdehyde and Myeloperoxidase, and a marked decrease in antioxidant Glutathione. At this time severe reductions in the cerebral blood flow (CBF) was seen together with increased blood-brain barrier (BBB) breakdown and brain edema formation. These pathophysiological responses were exacerbated in NPs treated heat-stressed animals. Pretreatment with cerebrolysin (2.5 mL/kg, i.v.) once daily for 3 days significantly attenuated the oxidative stress, BBB breakdown and brain edema and improved CBF in the heat stressed group. The other drugs were least effective on brain pathology following heat stroke. However, in NPs treated heat stressed animals 5 mL/kg conventional cerebrolysin and 2.5 mL/kg nanowired cerebrolysin is needed to attenuate oxidative stress, BBB breakdown, brain edema and to improve CBF. Interestingly, the other drugs even in higher doses used are unable to alter brain pathologies in NPs and heat stress. These observations are the first to demonstrate that cerebrolysin is the most superior antioxidant and anti-ischemic drug in NPs exposed heat stroke, not reported earlier. © 2021 Elsevier B.V.
Upregulation of hemeoxygenase enzymes HO-1 and HO-2 following ischemia-reperfusion injury in connection with experimental cardiac arrest and cardiopulmonary resuscitation: Neuroprotective effects of methylene blue
(Elsevier B.V., 2021) Lars Wiklund; Aruna Sharma; Ranjana Patnaik; Dafin F. Muresanu; Seaab Sahib; Z. Ryan Tian; Rudy J. Castellani; Ala Nozari; José Vicente Lafuente; Hari Shanker Sharma
Oxidative stress plays an important role in neuronal injuries after cardiac arrest. Increased production of carbon monoxide (CO) by the enzyme hemeoxygenase (HO) in the brain is induced by the oxidative stress. HO is present in the CNS in two isoforms, namely the inducible HO-1 and the constitutive HO-2. Elevated levels of serum HO-1 occurs in cardiac arrest patients and upregulation of HO-1 in cardiac arrest is seen in the neurons. However, the role of HO-2 in cardiac arrest is not well known. In this review involvement of HO-1 and HO-2 enzymes in the porcine brain following cardiac arrest and resuscitation is discussed based on our own observations. In addition, neuroprotective role of methylene blue- an antioxidant dye on alterations in HO under in cardiac arrest is also presented. The biochemical findings of HO-1 and HO-2 enzymes using ELISA were further confirmed by immunocytochemical approach to localize selective regional alterations in cardiac arrest. Our observations are the first to show that cardiac arrest followed by successful cardiopulmonary resuscitation results in significant alteration in cerebral concentrations of HO-1 and HO-2 levels indicating a prominent role of CO in brain pathology and methylene blue during CPR followed by induced hypothermia leading to superior neuroprotection after return of spontaneous circulation (ROSC), not reported earlier. © 2021 Elsevier B.V.