RESUMEN
Sleep deprivation is quite frequent in military during combat, intelligence gathering or peacekeeping operations. Even one night of sleep deprivation leads to accumulation of amyloid beta peptide burden that would lead to precipitation of Alzheimer's disease over the years. Thus, efforts are needed to slow down or neutralize accumulation of amyloid beta peptide (AßP) and associated Alzheimer's disease brain pathology including phosphorylated tau (p-tau) within the brain fluid environment. Sleep deprivation also alters serotonin (5-hydroxytryptamine) metabolism in the brain microenvironment and impair upregulation of several neurotrophic factors. Thus, blockade or neutralization of AßP, p-tau and serotonin in sleep deprivation may attenuate brain pathology. In this investigation this hypothesis is examined using nanodelivery of cerebrolysin- a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies against AßP, p-tau and serotonin (5-hydroxytryptamine, 5-HT). Our observations suggest that sleep deprivation induced pathophysiology is significantly reduced following nanodelivery of cerebrolysin together with monoclonal antibodies to AßP, p-tau and 5-HT, not reported earlier.
Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Humanos , Péptidos beta-Amiloides , Enfermedad de Alzheimer/metabolismo , Serotonina/metabolismo , Privación de Sueño/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Encéfalo/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Factores de Crecimiento Nervioso/uso terapéuticoRESUMEN
Alzheimer's disease is one of the devastating neurodegenerative diseases affecting mankind worldwide with advancing age mainly above 65 years and above causing great misery of life. About more than 7 millions are affected with Alzheimer's disease in America in 2023 resulting in huge burden on health care system and care givers and support for the family. However, no suitable therapeutic measures are available at the moment to enhance quality of life to these patients. Development of Alzheimer's disease may reflect the stress burden of whole life inculcating the disease processes of these neurodegenerative disorders of the central nervous system. Thus, new strategies using nanodelivery of suitable drug therapy including antibodies are needed in exploring neuroprotection in Alzheimer's disease brain pathology. In this chapter role of stress in exacerbating Alzheimer's disease brain pathology is explored and treatment strategies are examined using nanotechnology based on our own investigation. Our observations clearly show that restraint stress significantly exacerbate Alzheimer's disease brain pathology and nanodelivery of a multimodal drug cerebrolysin together with monoclonal antibodies (mAb) to amyloid beta peptide (AßP) together with a serotonin 5-HT6 receptor antagonist SB399885 significantly thwarted Alzheimer's disease brain pathology exacerbated by restraint stress, not reported earlier. The possible mechanisms and future clinical significance is discussed.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Anciano , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Serotonina , Calidad de Vida , Encéfalo/patologíaRESUMEN
Stress is one of the most serious consequences of life leading to several chronic diseases and neurodegeneration. Recent studies show that emotional stress and other kinds of anxiety and depression adversely affects Parkinson's disease symptoms. However, the details of how stress affects Parkinson's disease is still not well known. Traumatic brain injury, stroke, diabetes, post-traumatic stress disorders are well known to modify the disease precipitation, progression and persistence. However, show stress could influence Parkinson's disease is still not well known. The present investigation we examine the role of immobilization stress influencing Parkinson's disease brain pathology in model experiments. In ore previous report we found that mild traumatic brain injury exacerbate Parkinson's disease brain pathology and nanodelivery of dl-3-n-butylphthalide either alone or together with mesenchymal stem cells significantly attenuated Parkinson's disease brain pathology. In this chapter we discuss the role of stress in exacerbating Parkinson's disease pathology and nanowired delivery of dl-3-n-butylphthalide together with monoclonal antibodies to alpha synuclein (ASNC) is able to induce significant neuroprotection. The possible mechanisms of dl-3-n-butylphthalide and ASNC induced neuroprotection and suitable clinical therapeutic strategy is discussed.
Asunto(s)
Enfermedad de Parkinson , Distrés Psicológico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , alfa-Sinucleína , Neuroprotección , Anticuerpos , Encéfalo/metabolismoRESUMEN
Concussive head injury (CHI) is one of the major risk factors for developing Parkinson's disease in later life of military personnel affecting lifetime functional and cognitive disturbances. Till date no suitable therapies are available to attenuate CHI or PD induced brain pathology. Thus, further exploration of novel therapeutic agents are highly warranted using nanomedicine in enhancing the quality of life of veterans or service members of US military. Since PD or CHI induces oxidative stress and perturbs neurotrophic factors regulation associated with phosphorylated tau (p-tau) deposition, a possibility exists that nanodelivery of agents that could enhance neurotrophic factors balance and attenuate oxidative stress could be neuroprotective in nature. In this review, nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies to neuronal nitric oxide synthase (nNOS) with p-tau antibodies was examined in PD following CHI in model experiments. Our results suggest that combined administration of nanowired antibodies to nNOS and p-tau together with cerebrolysin significantly attenuated CHI induced exacerbation of PD brain pathology. This combined treatment also has beneficial effects in CHI or PD alone, not reported earlier.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Óxido Nítrico Sintasa de Tipo I , Calidad de Vida , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Encéfalo/patología , Factores de Crecimiento Nervioso , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
dl-3-n-Butylphthalide is a potent synthetic Chinese celery extract that is highly efficient in inducing neuroprotection in concussive head injury (CHI), Parkinson's disease, Alzheimer's disease, stroke as well as depression, dementia, anxiety and other neurological diseases. Thus, there are reasons to believe that dl-3-n-butylphthalide could effectively prevent Alzheimer's disease brain pathology. Military personnel during combat operation or veterans are often the victims of brain injury that is a major risk factor for developing Alzheimer's disease in their later lives. In our laboratory we have shown that CHI exacerbates Alzheimer's disease brain pathology and reduces the amyloid beta peptide (AßP) inactivating enzyme neprilysin. We have used TiO2 nanowired-dl-3-n-butylphthalide in attenuating Parkinson's disease brain pathology exacerbated by CHI. Nanodelivery of dl-3-n-butylphthalide appears to be more potent as compared to the conventional delivery of the compound. Thus, it would be interesting to examine the effects of nanowired dl-3-n-butylphthalide together with nanowired delivery of neprilysin in Alzheimer's disease model on brain pathology. In this investigation we found that nanowired delivery of dl-3-n-butylphthalide together with nanowired neprilysin significantly attenuated brain pathology in Alzheimer's disease model with CHI, not reported earlier. The possible mechanism and clinical significance is discussed based on the current literature.
Asunto(s)
Enfermedad de Alzheimer , Conmoción Encefálica , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Conmoción Encefálica/complicaciones , Conmoción Encefálica/patología , Péptidos beta-Amiloides , Neprilisina/uso terapéutico , Neuroprotección , Enfermedad de Parkinson/complicaciones , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking that is about 12.8% higher than civilian populations. Nicotine smoking triggers oxidative stress and are linked to several neurodegenerative diseases such as Alzheimer's disease. Nicotine neurotoxicity induces significant depression and oxidative stress in the brain leading to neurovascular damages and brain pathology. Thus, details of nicotine neurotoxicity and factors influencing them require additional investigations. In this review, effects of engineered nanoparticles from metals Ag and Cu (50-60 nm) on nicotine neurotoxicity are discussed with regard to nicotine smoking. Military personnel often work in the environment where chances of nanoparticles exposure are quite common. In our earlier studies, we have shown that nanoparticles alone induces breakdown of the blood-brain barrier (BBB) and exacerbates brain pathology in animal models. In present investigation, nicotine exposure in with Ag or Cu nanoparticles intoxicated group exacerbated BBB breakdown, induce oxidative stress and aggravate brain pathology. Treatment with nanowired H-290/51 a potent chain-breaking antioxidant together with nanowired ondansetron, a potent 5-HT3 receptor antagonist significantly reduced oxidative stress, BBB breakdown and brain pathology in nicotine exposure associated with Ag or Cu nanoparticles intoxication. The functional significance of this findings and possible mechanisms of nicotine neurotoxicity are discussed based on current literature.
Asunto(s)
Edema Encefálico , Nanopartículas , Fármacos Neuroprotectores , Animales , Humanos , Ondansetrón/farmacología , Antioxidantes/farmacología , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Nicotina/farmacología , Neuroprotección , Fármacos Neuroprotectores/farmacología , EncéfaloRESUMEN
Hallmark of Alzheimer's disease include amyloid beta peptide and phosphorylated tau deposition in brain that could be aggravated following traumatic of concussive head injury. However, amyloid beta peptide or p-tau in spinal cord following injury is not well known. In this investigation we measured amyloid beta peptide and p-tau together with tumor necrosis factor-alpha (TNF-α) in spinal cord and brain following 48 h after spinal cord injury in relation to the blood-spinal cord and blood-brain barrier, edema formation, blood flow changes and cell injury in perifocal regions of the spinal cord and brain areas. A focal spinal cord injury was inflicted over the right dorsal horn of the T10-11 segment (4 mm long and 2 mm deep) and amyloid beta peptide and p-tau was measured in perifocal rostral (T9) and caudal (T12) spinal cord segments as well as in the brain areas. Our observations showed a significant increase in amyloid beta peptide in the T9 and T12 segments as well as in remote areas of brain and spinal cord after 24 and 48 h injury. This is associated with breakdown of the blood-spinal cord (BSCB) and brain barriers (BBB), edema formation, reduction in blood flow and cell injury. After 48 h of spinal cord injury elevation of amyloid beta peptide, phosphorylated tau (p-tau) and tumor necrosis factor-alpha (TNF-α) was seen in T9 and T12 segments of spinal cord in cerebral cortex, hippocampus and brain stem regions associated with microglial activation as seen by upregulation of Iba1 and CD86. Repeated nanowired delivery of cerebrolysin topically over the traumatized segment repeatedly together with monoclonal antibodies (mAb) to amyloid beta peptide (AßP), p-tau and TNF-α significantly attenuated amyloid beta peptide, p-tau deposition and reduces Iba1, CD68 and TNF-α levels in the brain and spinal cord along with blockade of BBB and BSCB, reduction in blood flow, edema formation and cell injury. These observations are the first to show that spinal cord injury induces Alzheimer's disease like symptoms in the CNS, not reported earlier.
Asunto(s)
Enfermedad de Alzheimer , Traumatismos de la Médula Espinal , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Anticuerpos Monoclonales , Edema , Médula Espinal/irrigación sanguínea , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Factor de Necrosis Tumoral alfa , Animales , Ratas , Nanocables/uso terapéuticoRESUMEN
Military personnel are often victims of spinal cord injury resulting in lifetime disability and decrease in quality of life. However, no suitable therapeutic measures are still available to restore functional disability or arresting the pathophysiological progression of disease in victims for leading a better quality of life. Thus, further research in spinal cord injury using novel strategies or combination of available neuroprotective drugs is urgently needed for superior neuroprotection. In this regard, our laboratory is engaged in developing TiO2 nanowired delivery of drugs, antibodies and enzymes in combination to attenuate spinal cord injury induced pathophysiology and functional disability in experimental rodent model. Previous observations show that histamine antagonists or antioxidant compounds when given alone in spinal cord injury are able to induce neuroprotection for short periods after trauma. In this investigation we used a combination of histaminergic drugs with antioxidant compound H-290/51 using their nanowired delivery for neuroprotection in spinal cord injury of longer duration. Our observations show that a combination of H3 receptor inverse agonist BF-2549 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury. These observations suggests that histamine receptors are involved in the pathophysiology of spinal cord injury and induce superior neuroprotection in combination with an inhibitor of lipid peroxidation H-290/51, not reported earlier. The possible mechanisms and significance of our findings in relation to future clinical approaches in spinal cord injury is discussed.
Asunto(s)
Nanocables , Receptores Histamínicos H3 , Traumatismos de la Médula Espinal , Humanos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Agonismo Inverso de Drogas , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/uso terapéutico , Neuroprotección , Calidad de Vida , Receptores Histamínicos H3/uso terapéutico , Receptores Histamínicos H4RESUMEN
Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer's disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AßP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AßP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales , Encéfalo , Neuroprotección , Privación de Sueño , Factor de Necrosis Tumoral alfa/inmunología , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacología , Proteínas tau/inmunologíaRESUMEN
Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AßP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AßP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that 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 monoclonal antibodies (mAb) to AßP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AßP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.
Asunto(s)
Enfermedad de Parkinson , Receptores Histamínicos H3 , Humanos , alfa-Sinucleína , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales/farmacología , Encéfalo , Agonismo Inverso de Drogas , Histamina , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Histamínicos H4 , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacologíaRESUMEN
dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson's disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO2 nanowired dl-NBP with MSCs and mAb to ASNC with TDP-43 induced superior neuroprotection in CHI induced exacerbation of brain pathology in PD, not reported earlier.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Células Madre Mesenquimatosas , Nanocables , Fármacos Neuroprotectores , Enfermedad de Parkinson , Humanos , Neuroprotección , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína , Anticuerpos Monoclonales , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Nanocables/química , Proteínas de Unión al ADNRESUMEN
Military personnel are often exposed to silica dust during combat operations across the globe. Exposure to silica dust in US military or service personnel could cause Desert Strom Pneumonitis also referred to as Al Eskan disease causing several organs damage and precipitate autoimmune dysfunction. However, the effects of microfine particles of sand inhalation-induced brain damage on the pathophysiology of traumatic brain or spinal cord injury are not explored. Previously intoxication of silica nanoparticles (50-60 nm size) is shown to exacerbates spinal cord injury induces blood-spinal cord barrier breakdown, edema formation and cellular changes. However, the mechanism of silica nanoparticles-induced cord pathology is still not well known. Spinal cord injury is well known to alter serotonin (5-hydroxytryptamine) metabolism and induce oxidative stress including upregulation of nitric oxide synthase and tumor necrosis factor alpha. This suggests that these agents are involved in the pathophysiology of spinal cord injury. In this review, we examined the effects of combined nanowired delivery of monoclonal antibodies to neuronal nitric oxide synthase (nNOS) together with tumor necrosis factor alpha (TNF-α) antibodies and a potent antioxidant H-290/51 to induce neuroprotection in spinal cord injury associated with silica nanoparticles intoxication. Our results for the first time show that co-administration of nanowired delivery of antibodies to nNOS and TNF-α with H-290/51 significantly attenuated silica nanoparticles-induced exacerbation of spinal cord pathology, not reported earlier.
Asunto(s)
Antioxidantes , Nanocables , Traumatismos de la Médula Espinal , Humanos , Anticuerpos Monoclonales , Óxido Nítrico Sintasa de Tipo II/inmunología , Dióxido de Silicio/efectos adversos , Dióxido de Silicio/farmacología , Factor de Necrosis Tumoral alfa/inmunología , Nanocables/química , Nanopartículas/efectos adversos , Nanopartículas/químicaRESUMEN
Concussive head injury (CHI) is one of the major risk factors in developing Alzheimer's disease (AD) in military personnel at later stages of life. Breakdown of the blood-brain barrier (BBB) in CHI leads to extravasation of plasma amyloid beta protein (ΑßP) into the brain fluid compartments precipitating AD brain pathology. Oxidative stress in CHI or AD is likely to enhance production of nitric oxide indicating a role of its synthesizing enzyme neuronal nitric oxide synthase (NOS) in brain pathology. Thus, exploration of the novel roles of nanomedicine in AD or CHI reducing NOS upregulation for neuroprotection are emerging. Recent research shows that stem cells and neurotrophic factors play key roles in CHI-induced aggravation of AD brain pathologies. Previous studies in our laboratory demonstrated that CHI exacerbates AD brain pathology in model experiments. Accordingly, it is quite likely that nanodelivery of NOS antibodies together with cerebrolysin and mesenchymal stem cells (MSCs) will induce superior neuroprotection in AD associated with CHI. In this review, co-administration of TiO2 nanowired cerebrolysin - a balanced composition of several neurotrophic factors and active peptide fragments, together with MSCs and monoclonal antibodies (mAb) to neuronal NOS is investigated for superior neuroprotection following exacerbation of brain pathology in AD exacerbated by CHI based on our own investigations. Our observations show that nanowired delivery of cerebrolysin, MSCs and neuronal NOS in combination induces superior neuroprotective in brain pathology in AD exacerbated by CHI, not reported earlier.
Asunto(s)
Enfermedad de Alzheimer , Traumatismos Craneocerebrales , Células Madre Mesenquimatosas , Fármacos Neuroprotectores , Humanos , Enfermedad de Alzheimer/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico Sintasa de Tipo I/metabolismo , Anticuerpos Monoclonales/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Células Madre Mesenquimatosas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Traumatismos Craneocerebrales/tratamiento farmacológico , Traumatismos Craneocerebrales/metabolismo , Traumatismos Craneocerebrales/patologíaRESUMEN
Blast brain injury (bBI) following explosive detonations in warfare is one of the prominent causes of multidimensional insults to the central nervous and other vital organs injury. Several military personnel suffered from bBI during the Middle East conflict at hot environment. The bBI largely occurs due to pressure waves, generation of heat together with release of shrapnel and gun powders explosion with penetrating and/or impact head trauma causing multiple brain damage. As a result, bBI-induced secondary injury causes breakdown of the blood-brain barrier (BBB) and edema formation that further results in neuronal, glial and axonal injuries. Previously, we reported endocrine imbalance and influence of diabetes on bBI-induced brain pathology that was significantly attenuated by nanowired delivery of cerebrolysin in model experiments. Cerebrolysin is a balanced composition of several neurotrophic factors, and active peptide fragment is capable of neuroprotection in several neurological insults. Exposure to heat stress alone causes BBB damage, edema formation and brain pathology. Thus, it is quite likely that hot environment further exacerbates the consequences of bBI. Thus, novel therapeutic strategies using nanodelivery of stem cell and cerebrolysin may further enhance superior neuroprotection in bBI at hot environment. Our observations are the first to show that combined nanowired delivery of mesenchymal stem cells (MSCs) and cerebrolysin significantly attenuated exacerbation of bBI in hot environment and induced superior neuroprotection, not reported earlier. The possible mechanisms of neuroprotection with MSCs and cerebrolysin in bBI are discussed in the light of current literature.
Asunto(s)
Traumatismos por Explosión , Lesiones Encefálicas , Células Madre Mesenquimatosas , Humanos , Explosiones , EncéfaloRESUMEN
Environmental temperature adversely affects the outcome of concussive head injury (CHI)-induced brain pathology. Studies from our laboratory showed that animals reared at either cold environment or at hot environment exacerbate brain pathology following CHI. Our previous experiments showed that nanowired delivery of oxiracetam significantly attenuated CHI-induced brain pathology and associated neurovascular changes. Military personnel are the most susceptible to CHI caused by explosion, blasts, missile or blunt head trauma leading to lifetime functional and cognitive impairments affecting the quality of life. Severe CHI leads to instant death and/or lifetime paralysis. Military personnel engaged in combat operations are often subjected to extreme high or low environmental temperature zones across the globe. Thus, further exploration of novel therapeutic agents at cold or hot ambient temperatures following CHI are the need of the hour. CHI is also a major risk factor for developing Alzheimer's disease by enhancing amyloid beta peptide deposits in the brain. In this review, effect of hot environment on CHI-induced brain pathology is discussed. In addition, whether nanodelivery of oxiracetam together with neprilysin and monoclonal antibodies (mAb) to amyloid beta peptide and p-tau could lead to superior neuroprotection in CHI is explored. Our results show that co-administration of oxiracetam with neprilysin and mAb to AßP and p-tau significantly induced superior neuroprotection following CHI in hot environment, not reported earlier.
Asunto(s)
Anticuerpos Monoclonales , Lesiones Traumáticas del Encéfalo , Neprilisina , Pirrolidinas , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Animales , Calor , Pirrolidinas/administración & dosificación , Humanos , Nanocables/química , Encéfalo/patología , Neprilisina/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Neuroprotección/efectos de los fármacosRESUMEN
Military personnel are often exposed to hot environments either for combat operations or peacekeeping missions. Hot environment is a severe stressful situation leading to profound hyperthermia, fatigue and neurological impairments. To avoid stressful environment, some people frequently use methamphetamine (METH) or other psychostimulants to feel comfortable under adverse situations. Our studies show that heat stress alone induces breakdown of the blood-brain barrier (BBB) and edema formation associated with reduced cerebral blood flow (CBF). On the other hand, METH alone induces hyperthermia and neurotoxicity. These effects of METH are exacerbated at high ambient temperatures as seen with greater breakdown of the BBB and brain pathology. Thus, a combination of METH use at hot environment may further enhance the brain damage-associated behavioral dysfunctions. METH is well known to induce severe oxidative stress leading to brain pathology. In this investigation, METH intoxication at hot environment was examined on brain pathology and to explore suitable strategies to induce neuroprotection. Accordingly, TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant in combination with mesenchymal stem cells (MSCs), is investigated in attenuating METH-induced brain damage at hot environment in model experiments. Our results show that nanodelivery of H-290/51 with MSCs significantly enhanced CBF and reduced BBB breakdown, edema formation and brain pathology following METH exposure at hot environment. These observations are the first to point out that METH exacerbated brain pathology at hot environment probably due to enhanced oxidative stress, and MSCs attenuate these adverse effects, not reported earlier.
Asunto(s)
Encefalopatías , Células Madre Mesenquimatosas , Metanfetamina , Humanos , Antioxidantes , Estrés Oxidativo , Barrera HematoencefálicaRESUMEN
Military personnel during combat or peacekeeping operations are exposed to extreme climates of hot or cold environments for longer durations. Spinal cord injury is quite common in military personnel following central nervous system (CNS) trauma indicating a possibility of altered pathophysiological responses at different ambient temperatures. Our previous studies show that the pathophysiology of brain injury is exacerbated in animals acclimated to cold (5 °C) or hot (30 °C) environments. In these diverse ambient temperature zones, trauma exacerbated oxidative stress generation inducing greater blood-brain barrier (BBB) permeability and cell damage. Extracts of Ginkgo biloba EGb-761 and BN-52021 treatment reduces brain pathology following heat stress. This effect is further improved following TiO2 nanowired delivery in heat stress in animal models. Several studies indicate the role of EGb-761 in attenuating spinal cord induced neuronal damages and improved functional deficit. This is quite likely that these effects are further improved following nanowired delivery of EGb-761 and BN-52021 with cerebrolysin-a balanced composition of several neurotrophic factors and peptide fragments in spinal cord trauma. In this review, TiO2 nanowired delivery of EGb-761 and BN-52021 with nanowired cerebrolysin is examined in a rat model of spinal cord injury at cold environment. Our results show that spinal cord injury aggravates cord pathology in cold-acclimated rats and nanowired delivery of EGb-761 and BN-52021 with cerebrolysin significantly induced superior neuroprotection, not reported earlier.
Asunto(s)
Bilobálidos , Ginkgo biloba , Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Animales , Ratas , Frío , Sistemas de Liberación de Medicamentos , Nanocables , Fármacos Neuroprotectores/uso terapéutico , Extractos Vegetales/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , ChinaRESUMEN
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 (1mg/kg, i.p.) or CLBPT (1mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25µL) 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.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Cuerpo Estriado , Histamina , Humanos , Imidazoles , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Histamínicos H4 , Tiourea/análogos & derivadosRESUMEN
Military personnel are often exposed to high altitude (HA, ca. 4500-5000m) 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 (150mg/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.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Metanfetamina , Fármacos Neuroprotectores , Altitud , Animales , Antioxidantes , Barrera Hematoencefálica , Encéfalo , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , RatasRESUMEN
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 (50-60nm, 50mg/kg, i.p./day for 7 days). Rats were subjected to 4h heat stress (HS) in a biological oxygen demand incubator at 38°C (Relative Humidity 45-47%; Wind velocity 22.4-25.6cm/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 (2.5mL/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 5mL/kg conventional cerebrolysin and 2.5mL/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.