Current Pharmaceutical Design - Volume 13, Issue 18, 2007

Neuroprotection: Non-Neural Cells Regulate Neuronal Functions The term “Neuroprotection” normally denotes rescue of nerve cells. However, the non-neural cells, i.e., glial cells and endothelial cells are equally important for brain function in normal and in pathological conditions [1,2]. The number of glial cells and endothelial cells far exceeds the number of neural cells in the CNS [2,3]. In spite of this fact, most attention is still focused to rescue nerve cells following CNS injuries and the role of non-neural cells in neurodegeneration or neuroprotection is largely ignored. Thus, the term “neuroprotection” is normally misleading as neurons are in the minority in the CNS and their function depends on the survival of non-neural cells and vice versa. To restore the normal function of the CNS by pharmacological manipulation, revival of glial cells and endothelial cell functions are equally important [4-6]. The nerve cell function is largely dependent on the normal endothelial cell and glial function. Thus, it is imperative that in pathological conditions, reducing damage to endothelial cells and/or glial cells by pharmacological agents will improve nerve cell function. Alternatively, glial cells, endothelial cells are all working to maintain and regulate neuronal function in health and disease [7,8]. Taken together, it appears that both the neural and non-neural components of the CNS are working in synergy for maintaining normal brain function and alterations in any neural or non-neural component will have severe impact on CNS structure and function. Blood-Brain vs. Brain Blood Barriers Our CNS is well equipped with the blood-brain barrier that is anatomically located within the endothelial cells of the brain microvasculature [1]. It is assumed that both the luminal and the abluminal cell membranes of the endothelium are equally “tight” to maintain an effective barrier between blood to brain and brain to blood [1,2]. Interestingly, the endothelial cell function and membrane transport from brain to blood (brain-blood barrier) in relation to neurodegeneration and neurorepair mechanisms are still largely ignored [see7,8]. Thus, it is still unclear whether luminal barrier disruption always accompanied with identical damage to the abluminal barrier function. However, there are reasons to believe that when luminal membrane is permeable, the abluminal side is also showing some alteration in the membrane function. A direct evidence to support or reject this hypothesis is still lacking. Studies carried out in our laboratory suggest that hyperthermia induced breakdown of the blood-brain barrier is also associated with a leaky brain blood-barrier [5,9]. Thus, serotonin transport occurs from brain to the blood causing a massive accumulation of the amine in the circulation leading to a generalized and widespread disruption of the blood-brain barrier [9]. This large increase in plasma serotonin is largely prevented by destruction of the serotoninergic neurons into the brain [see 5,9]. This treatment did not allow brain serotonin to increase and thus, the plasma serotonin concentration is much lower resulting in a minor breakdown of the blood-brain barrier in hyperthermia [5]. This suggests that various endogenous substances, e.g., cytokines, growth factors, growth hormone etc. are released from brain in extra quantity following injury that could be transported into the blood stream to have a generalized effect on the cerebral circulation and/or brain function. However, this is entirely a new subject and requires additional investigation in details to achieve better neuroprotection in future. In this volume, the term “Neuroprotection” is employed in its widest sense to include protection of all the “neural” and “nonneural” components of the CNS. This issue highlights the role of non-neural cells; especially the function of endothelial cells and its surrounding glial cells in neurodegeneration and repair process.......

Neural precursors that are found in the subventricular zone and dentate gyrus of the adult brain might be useful in cell replacement therapies for neurological disorders. The development of pharmacological drugs that would increase production of new neurons would be facilitated by identification of the endogenous or natural molecular regulators of adult neurogenesis in vivo. This review discusses known endogenous regulators of the cellular events that are required for functional neurogenesis in adult animals. These steps include proliferation of stem cells and progenitors, survival and migration of new neuroblasts, differentiation into mature neurons and functional integration into existing neural circuits. Various treatments have been shown to enhance neurogenesis and neuroblast migration in adult rodents, raising the possibility that these resident neural stem cells could be used to treat people with neurological disorders. This review also highlights some of the potential problems and limitations that may arise when considering such therapies.

Several neurotrophic factors are known to induce neuroprotection in traumatic injuries to the central nervous system (CNS). However, many neurotrophins are unable to attenuate cell death following CNS injuries. New data generated in our laboratory show that a suitable combination of neurotrophic factors may enhance the neuroprotective efficacy of neurotrophins on cell and tissue injury and improve sensory motor functions. This novel aspect of neurotrophins treatment in combination in spinal cord injury (SCI) induced behavioral dysfunctions and spinal cord pathology is examined in a rat model. Our investigations suggest that a suitable combination of neurotrophins will attenuate both neural and non-neural (glial cells and endothelial cells) damage in SCI leading to enhanced neuroprotection. The possible cellular and molecular mechanisms of synergistic effects of some neurotrophins in combination are still speculative and require further investigation.

The c-Jun N-terminal kinases (JNK) belong to the subfamily of mitogen-activated protein kinase (MAPK). JNK is an important transducing enzyme that is involved in many facets of cellular regulation including gene expression, cell proliferation and programmed cell death. The activation of JNK pathways is critical for naturally occurring cell death during development as well as for pathological death associated with neurodegenerative diseases. Initial research concentrated on defining the components and organization of JNK signalling cascades, but more recent studies see JNK as a target to prevent cell death. Several in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with neuronal death in Parkinson's and Alzheimer's disease. So efforts are now aimed at developing chemical inhibitors of this pathway. These have proved effective in vivo, reducing brain damage and some of the symptoms of arthritis in animal models. An alternative cell penetrating peptide approach is now available, with the identification of the JNK permeable peptide inhibitor, which modifies JNK action rather than activation, preventing neuronal death with unprecedented specificity and efficacy in several experimental conditions, including two animal models of ischemia. In this review we examine in detail the role of JNK in neurodegeneration, particularly in Alzheimer's and Parkinson's disease. The possibility of intervention on the JNK pathway as a therapeutic approach is also illustrated.

Shut-down of translation is a global stress response required to block synthesis of proteins that cannot be correctly folded and thereby reduce the work load of the folding machinery, a primary target of the pathological process triggered by severe forms of stress. The short-term control of protein synthesis involves alterations in the activity of initiation factors mediated through changes in their phosphorylation states, the alpha subunit of eukaryotic initiation factor 2 being a key player in this process. While the stress-induced shut-down of translation is viewed as a protective response, the inability of vulnerable cells to restore protein synthesis after being exposed to a severe form of stress is a pathological process because it blocks the translation of messages coding for protective proteins required for restoration of function. In models of cerebral ischemia, prolonged suppression of protein synthesis is therefore always associated with extensive cell death. Endoplasmic reticulum (ER) dysfunction has been identified as the mechanism underlying ischemia-induced suppression of protein synthesis. GADD34 is a protein that plays a pivotal role in the recovery of cells from shut-down of translation induced by ER stress. After transient ischemia, a rise in GADD34 protein levels has been found in resistant but not in vulnerable cells. Knowledge of the mechanisms activated in resistant cells to restore protein synthesis after severe stress will help open up new avenues for therapeutic strategies to combat various disorders of the brain associated with impairment of the translational machinery.

The psychostimulants, morphine and methamphetamine are well known drugs of abuse that induce brain pathology and/or neurodegeneration resulting in a huge burden on our society. The possible mechanisms of psychostimulants induced neuropathology and neurodegeneration are still not well known. The drugs of abuse results in profound hyperthermia and widespread alterations in neurochemical metabolism in the central nervous system (CNS). It appears that psychostimulants induced hyperthermia and/or release of neurochemicals influence the blood-brain barrier (BBB) dysfunction leading to brain pathology. The drugs of abuse also induce oxidative stress resulting in generation of free radicals and lipid peroxidation. Thus, further research is needed to understand the basic function of BBB disruption and temperature regulation by psychostimulants and to modify them pharmacologically to attenuate brain dysfunction and neuropathology. This review is focused on the problems of morphine and methamphetamine induced hyperthermia and their effects on breakdown of the BBB function leading to brain damage. Works done in our laboratory suggest that hyperthermia caused by these drugs is responsible for BBB disruption and neurodegeneration. This hypothesis is further supported by our observation that pretreatment with a portent antioxidant compound H-290/51 attenuates the BBB disruption and induces marked neuroprotection following morphine induced withdrawal and methamphetamine induced neurotoxicity. The possible mechanisms and functional significance of these findings are discussed.

Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in Parkinson 's disease (PD): While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. It was shown that following an acute exposure to the neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other toxins the degenerative process continues for years in absence of the toxin. Reactive microglia has been observed in the substantia nigra of patients with PD, indicating that this inflammatory process might aggravate neurodegeneration. By releasing various kinds of noxious factors such as cytokines or proinflammatory molecules microglia may damage CNS cells. The stimuli triggering microgliosis in Parkinsonian syndromes are unknown so far: However, analysis of neuronal loss in PD patients shows that it is not uniform but that neurons containing neuromelanin (NM) are predominantly involved. We hypothesized that extraneuronal melanin might trigger microgliosis, microglial chemotaxis and microglial activation in PD with subsequent release of neurotoxic mediators. The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor kappa B (NF-κB) via phosphorylation and degradation of the inhibitor protein κB (IκB), and led to an upregulation of TNF-α, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinson's disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.