Clinical neuroprotection and secondary neuronal injury mechanisms

Cerebral injury is a common cause of severe morbidity and mortality and is frequently encountered by anaesthetists and intensive care physicians in clinical practice. Insults may arise from a variety of medical and surgical conditions, including stroke, subarachnoid haemorrhage, central nervous system infection, epilepsy, post cardiac arrest, and traumatic brain injury (TBI). Although the primary damage to brain tissue may be irreversible, aggressive early treatment may limit the ensuing secondary brain injury and reduce the risk of severe disability or death. Neuroprotection involves physiological, pharmacological and surgical interventions, initiated before the onset of ischaemia that can modify the cascade of events that lead to permanent cell damage when left unchecked.     

Clinical neuroprotection and secondary neuronal injury mechanisms

Multiple disease processes can ultimately lead to cerebral injury, a common cause of both severe morbidity and mortality in patients of all age groups. Cerebral injury is seen in a variety of both medical and surgical conditions, including stroke, subarachnoid haemorrhage, central nervous system infection, epilepsy, post cardiac arrest and, of course, traumatic brain injury.Although the primary damage to brain tissue may be irreversible, aggressive early physiological, pharmacological and surgical interventions may limit the ensuing secondary brain injury caused by ongoing ischaemia, and reduce the risk of severe disability or death.     

Clinical neuroprotection and secondary neuronal injury mechanisms

Anaesthetists and intensive care physicians commonly encounter brain injuries in their clinical practice. Cerebral insults may arise from traumatic brain injury, may follow cardiothoracic, vascular or major orthopaedic surgery, and are seen in medical conditions including subarachnoid haemorrhage, central nervous system infection, epilepsy and stroke. In all cases, neuronal injury may lead to severe disability or death; however, aggressive early treatment to prevent the mechanisms that lead to irreversible ischaemia and neuronal cell destruction can result in improvements in patient morbidity and mortality. Neuroprotection involves intervention initiated before the onset of an ischaemic event in an attempt to modify the cascade of biological events that follow ischaemia and thus limit permanent cell damage. Neuroresuscitation, on the other hand, refers to treatment aimed at restoring blood flow to cells that have already become exposed to an ischaemic insult.     

Medical management of head injury and neuroprotection

Head injury continues to cause significant mortality and morbidity despite the advances in early and late management and rehabilitation techniques. The extent and prognosis of brain injury are influenced by the primary impact and initiation of secondary mechanism. Outcome is also dependent on resuscitation and maintenance of cerebral oxygenation. The initial management is aimed at preventing secondary brain injury and identifying those patients who may benefit from surgical intervention. Continuing care is based on the careful and timely transfer to the appropriate intensive care environment where maintenance and monitoring of cerebral oxygenation are used. A variety of techniques involving the manipulation of both cerebral perfusion pressure and intracranial pressure are employed. There are a number of, as-yet, unproven techniques under examination for affecting cerebral metabolism to provide a degree of protection against further damage.     

Clinical neuroprotection and secondary neuronal injury mechanisms

Cerebral injury is a common cause of severe morbidity and mortality and is frequently encountered by anaesthetists and intensive care physicians in clinical practice. Insults may arise from a variety of medical and surgical conditions, including stroke, subarachnoid haemorrhage, central nervous system infection, epilepsy, post-cardiac arrest, and traumatic brain injury (TBI).Although the primary damage to brain tissue may be irreversible, aggressive early treatment may limit the ensuing secondary brain injury and reduce the risk of severe disability or death. Neuroprotection involves physiological, pharmacological and surgical interventions, initiated before the onset of ischaemia that can modify the cascade of events that lead to permanent cell damage when left unchecked.     

Opportunities for neuroprotection in traumatic brain injury

Traumatic injury of the brain in man is normally followed by little or no recovery of function by the lesioned tissue. Neuroprotective strategies employed in the acute period after traumatic CNS injury attempt to use pharmacological tools to reduce the progressive secondary injury processes that follow after the initial lesion occurs to limit overall tissue damage. Results from experimental animal studies using a variety of drugs that modulate neurotransmitter function, scavenge free radicals, or interfere with cell death cascades point toward many new opportunities for pharmacological intervention in the acute and subacute period after traumatic brain injury.     

Neuronal injury in chronic CNS inflammation

INTRODUCTION: Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system which is characterized by inflammatory demyelination and neurodegeneration. Neurological symptoms include sensory disturbances, optic neuritis, limb weakness, ataxia, bladder dysfunction, cognitive deficits and fatigue. PATHOPHYSIOLOGY: The inflammation process with MS is promoted by several inflammatory cytokines produced by the immune cells themselves and local resident cells like activated microglia. Consecutive damaging pathways involve the transmigration of activated B lymphocytes and plasma cells, which synthesize antibodies against the myelin sheath, boost the immune attack, and result in ultimate loss of myelin. Likewise, activated macrophages and microglia are present outside the lesions in the normal-appearing CNS tissue contributing to tissue damage. In parallel to inflammatory demyelination, axonal pathology occurs in the early phase which correlates with the number of infiltrating immune cells, and critically contributes to disease severity. The spectrum of neuronal white matter and cortical damage ranges from direct cell death to subtle neurodegenerative changes such as loss of dendritic ramification and the extent of neuronal damage is regarded as a critical factor for persisting neurological deficits. Under normal conditions, CNS microglia safeguards organ integrity by constantly scanning the tissue and responding rapidly to danger signals. The main task of microglial cells is to encapsulate dangerous foci and remove apoptotic cells and debris to protect the surrounding CNS tissue; this assists with tissue regeneration in toxin-induced demyelination. In the absence of lymphocytic inflammation and in the context of non-autoimmune, pathogen-associated triggered inflammation, microglial cells protect the neuronal compartment. These mechanisms seem to be inverted in MS and other chronic neurodegenerative disorders because activated microglia and peripherally derived macrophages are shifted towards a strongly pro-inflammatory phenotype and produce the proinflammatory cytokines TNF-α and interleukin (IL)1-β, as well as potentially neurotoxic substances including nitric oxide, oxygen radicals and proteolytic enzymes. Microglial silencing reduces clinical severity, demonstrating their active involvement in damage processes and in the immune attack against the CNS. In light of this, it is questionable whether microglia and monocyte-derived macrophages, the very last downstream effector cells in the immune reaction, actually have the capacity to influence their fate. It is more likely that the adaptive immune system orchestrates the attack against CNS cells and drives microglia and macrophages to attack oligodendrocytes and neurons. NEUROPROTECTIVE STRATEGIES: Currently, Glatiramer acetate (GA) and the interferon-β (IFN-β) variants are established as first-line disease modifying treatments that reduce the relapse rate, ameliorate relapse severity and delay the progression of disability in patients with relapsing-remitting MS. Similarily, sphingosine-1-phosphate (S1P) receptor agonists which influence lymphocyte migration through T cells-trapping in secondary lymphatic organs ameliorates astrogliosis and promotes remyelination by acting on S1P-receptors on astrocytes and oligodendrocytes. Ion channel blockers (e.g. sodium channel blockers), currently used for other indications, are now tested in neurodegenerative diseases to restore intracellular ion homeostasis in neurons. Axonal degeneration was significantly reduced and functional outcome was improved during treatment with Phenytoin, Flecainide and Lamotrigine. Although evidence for a direct protective effect on axons is still missing, additional immune-modulatory actions of sodium channel blockers on microglia and macrophages are likely available. In vitro-studies in axons subjected to anoxia in vitro or exposure to elevated levels of nitric oxide (NO) in vivo demonstrated the involvement of a direct effect on axons. As increased intracellular calcium levels contribute to axonal damage through activation of different enzymes such as proteases, blockade of voltage gated calcium channels is another promising target. For example, nitrendipin and bepridil ameliorate axonal loss and clinical symptoms in different models of chronic neurodegeneration. In addition to these exogenous neuroprotective patheways, endogenous neuroprotective mechanisms including neurotrophins, (re)myelination and, neurogenesis support restauration of neuronal integrity.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

Neuronal dysfunction in chronic spinal cord injury

This review describes the changes of spinal neuronal function that occur after a motor complete spinal cord injury (cSCI) in humans. In healthy subjects, polysynaptic spinal reflex (SR) evoked by non-noxious tibial nerve stimulation consists of an early SR component and rarely a late SR component. Soon after a cSCI, SR and locomotor activity are absent. After spinal shock; however, an early SR component re-appears associated with the recovery of locomotor activity in response to appropriate peripheral afferent input. Clinical signs of spasticity take place in the following months, largely as a result of non-neuronal changes. After around 1 year, the locomotor and SR activity undergo fundamental changes, that is, the electromyographic amplitude in the leg muscles during assisted locomotion exhaust rapidly, accompanied by a shift from early to dominant late SR components. The exhaustion of locomotor activity is also observed in non-ambulatory patients with an incomplete spinal cord injury (SCI). At about 1 year after injury, in most cSCI subjects the neuronal dysfunction is fully established and remains more or less stable in the following years. It is assumed that in chronic SCI, the patient's immobility resulting in a reduced input from supraspinal and peripheral sources leads to a predominance of inhibitory drive within spinal neuronal circuitries underlying locomotor pattern and SR generation. Training of spinal interneuronal circuits including the enhancement of an appropriate afferent input might serve as an intervention to prevent neuronal dysfunction after an SCI.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.     

脑缺血/再灌注损伤保护性药物的研究进展

临床中多采用药物对脑缺血,再灌注损伤进行预防与处理,以达到脑保护效果.现就药物的抗氧化作用、抗凋亡作用、减少血脑屏障的损伤及抑制钙离子超载等方面对近年来神经保护性药物的研究现状作一综述,为临床防治脑缺血/再灌注损伤提供理论依据.