Neurodegenerative injury

There are multiple mechanisms known to underlie the neuronal cell damage associated with injury or disease that at least theoretically could be targeted for pharmaceutical intervention. Currently however, there is no clinically available therapeutic agent that can reliably protect the brain from progressive neurodegenerative processes for sustained periods. Due to the extensive amount of preclinical research that has been conducted in recent years, there is a basis for optimism, however, it appears likely that some of these approaches will result in clinically effective therapeutic modalities in the near future. A short overview of some of the investigational approaches to combat neurodegeneration appears below. 

CXCR3 is expressed in the immnne system as two isoforms, CXCR3-A and CXCR3-B. It is an important chemokine receptor associated with varions inflammatory neurodegenerative diseases (e.g. multiple sclerosis) and other models of nenronal injury as reviewed by (Liu et al. 2005). 

Pratt, B. M. and McPherson, J. M. TGF-beta in the central nervous system potential roles in ischemic injury and neurodegenerative diseases. Cytokine Growth Factor Rev. 8 267-292,1997. 

Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli 576 Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli 576 Phospholipids in synaptic membranes are an important target in seizures, head injury, neurodegenerative diseases and cerebral ischemia 576 Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipids that act as messengers 576 Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second carbon of glycerol 577... 

This chapter surveys the neurochemistry of lipid messengers, as well as the mechanisms by which bioactive lipids accumulate upon stimulation in response to injury, cerebral ischemia, seizures, neurotrauma or neurodegen-erative diseases, and their significance in pathophysiology. Emphasis is placed on three groups of bioactive lipids AA and its metabolites, known collectively as eicosanoids PAF, a highly potent ether phospholipid and the newly identified DHA-derived mediator, neuroprotectin Dl. 

Moreover,bioactive lipids maybe considered dual messengers they modulate cell functions as messengers and they become part of the response of the nervous tissue to injury, broadly referred to as the inflammatory response. This response occurs in ischemia-reperfusion damage associated with stroke, various forms of neurotrauma, infectious diseases and neurodegenerative diseases such as Alzheimer s disease. Inflammation in the nervous system differs from that in other tissues. If the blood-brain barrier is broken, blood-borne inflammatory cells (e.g. polymorphonuclear leukocytes, monocytes, macrophages) invade the intercellular space and glial cells are activated, particularly microglia, which play a prominent role in the inflammatory response. These responses may... 

A broad variety of diseases may cause neuropathic pain. The majority of diseases associated with neuropathic pain involve the peripheral nervous system. These diseases include traumatic injuries hereditary, metabolic, inflammatory or paraneoplastic neuropathies and infections. However, neuropathic pain can also be caused by injuries or disorders affecting the spinal cord or the brain (central neuropathic pain) tumors stroke epilepsy and neurodegenerative disorders [20]. Genetic factors appear to contribute to inter-individual differences in the susceptibility to neuropathic pain. 

Bcl-2 B cell lymphoma protein 2 (Bcl-2) is a family of proteins that regulate apoptosis (programmed cell death). Apoptosis is a necessary process whereby aged or damaged cells are replaced by new cells. Dysfunction of the apoptosis process results in disease inhibition of apoptosis results in cancer, autoimmune disorder, and viral infection, whereas increased apoptosis gives rise to neurodegenerative disorders, myelodysplastic syndromes, ischemic injury, and toxin-induced liver disease. 

As previously discussed, the COX-2 inhibitors have selectivity for inhibition of the COX-2 enzyme, which has low constitutive activity but is highly inducible at sites of tissue injury. In addition to the peripheral role of COX-2 in inflammation, COX-2 may play an important role in the CNS. COX-2 is expressed constitutively in some excitatory neurons in the brain and spinal cord and is induced in traumatic brain injury such as that induced by ischemia and seizures. It has been hypothesized that COX-2 may also be involved in neurodegen-erative diseases, since COX-2 inhibitors have shown some positive effects in Alzheimer s disease. Thus, the mechanism of action of COX-2 inhibitors may involve brain and spinal cord sites as well as local sites of injury. 

The neurodegenerative disorders include (1) Alzheimer s disease, the most common cause of dementia, in which the neural injury is primarily in the hippocampus and cortex (2) Parkinson s disease, a disabling motor impairment disorder due to the loss of nigrostriatal dopamine neurons (3) Huntington s disease, a motor disease characterized by excessive and ab-... 

Indications Central nervous system disease, lysosome storage disease, neurodegenerative disease, spinal cord injury Technology Stem-cell therapy... 

StemCells, Inc. is developing a proprietary NSC product for cellular therapy, under license from NeuroSpheres Ltd., comprising well-characterized, normal human CNS stem cells (HuCNS-SCs) from brain tissue. HuCNS-SC is currently under investigation for the potential treatment of neurodegenerative disorders, particularly BD [180367], [540074]. Preclinical studies have been performed in various animal models of CNS diseases and injuries. Data from these studies has supported the therapeutic potential of HuCNS-SCs, and the therapy has recently been approved for a phase I clinical trial for the treatment of BD [629732]. 

Cellular therapy is the replacement of unhealthy or damaged cells or tissues with new ones. Because neurodegenerative diseases, cerebral strokes and traumatic injuries to the CNS produce neurological deficits that result from neuronal loss, cell therapy is a major area of investigation for the treatment of neurological diseases and injuries. 

Curtis, M.A., Eriksson, P.S., Faull, R.L. (2007b) Progenitor cells and adult neurogenesis in neurodegenerative diseases and injuries of the basal ganglia. Clin Exp Pharmacol Physiol 34, 528-32. 

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