Neuroregeneration

<center>Neurogenesis and Beyond – Brain Rejuvenation in Chronic Neurodegenerative and Acute Central Nervous System Diseases 
Ludwig Aigner 
Paracelsus Medical University, Salzburg, Austria </center>

Ageing populations are creating enormous challenges for healthcare providers worldwide, including large increases in age-associated diseases, such as dementias, neurodegenerative diseases and stroke. Moreover, elderly people can suffer traumatic central nervous system (CNS) injuries from simple falls. Endogenous repair mechanisms such as neurogenesis are currently the focus of intense research activities aiming to regenerate or to rejuvenate the aged and damaged brain.20,21 In treating TBI and other neurological diseases, understanding self-repair mechanisms such as neurogenesis allows attempts to rejuvenate the aged brain and to restore function after CNS injuries. An important aim of current research is increasing the levels of neurogenesis and to lowering the inflammatory load in the aged brain.

Initial work has shown that restoring function in the ageing brain is feasible. A proof of concept study demonstrated rejuvenation of the aged brain following exposure to blood from a younger individual.22 Current investigations aim to elucidate the role of transforming growth factor-β (TGF-β)23 on leukotriene signalling for use as a target for brain rejuvenation. In addition, Cerebrolysin, a neurotrophic peptide drug in development, has been shown to rejuvenate the aged and diseased brain,24 and thus offers considerable potential in the treatment of dementia, stroke and TBI. The pharmacological treatment of acute CNS lesions and spinal cord injury is also under investigation.

Several experimental treatments utilise restorative, regenerative and plasticity-enhancing approaches in the treatment of acute and neurodegenerative disorders. The usual failure of clinical trials in neurology can be attributed at least in part to their being focused solely on neuroprotection. Neuroprotection, however, is only a part of the complex rejuvenation process of the brain post-injury. The recovery from damage is based on natural, spontaneous processes leading to repair, regeneration and restoration of neurological structures and functions.25 Lateral ventricle neurogenesis is one example of such a natural process that can be further stimulated by pharmacological intervention.

In the experimental models of brain and spinal cord injuries, the leukotriene receptor antagonists (such as montelukast, an asthma treatment agent) reduce neuroinflammation, stimulate neurogenesis and improve functional outcomes in the aged brain as well as in models of spinal cord injury.26 Other experimental models show that Cerebrolysin induces structural plasticity in ageing brain and also restores synaptic density, neurogenesis, learning and memory in Alzheimer’s disease models in mice.27–29

Clinical data available to date suggest that Cerebrolysin is effective in the treatment of acute and neurodegenerative disorders.11,30,31 Further clinical investigations are warranted for Cerebrolysin in order to optimise already existing treatment protocols. The significance of treatment regimen optimisation is well illustrated by a granulocyte colony-stimulating factor trial, which failed to show efficacy due to the poor understanding of the biology of recovery processes with the resulting inadequate treatment protocol employed in the trial.32

<center>Neuroregeneration in Both Experimental Brain Injuries and Clinical Trials 
Wai Poon 
Professor and Chief in Neurosurgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong </center>

Clinical management of brain injuries has focused on the prevention of secondary insults and once disabling deficits are established, treatments have proved disappointing. Cell therapies have proved effective in animal models of brain injuries, both in molecular and behavioural terms.33,34 However, clinical trial data are needed to confirm these findings. In order to achieve meaningful clinical effects, improvements are needed in the quality of the cells and associated molecular factors.

TBI treatment developed by Dr Wai Poon’s team at the Prince of Wales Hospital in Hong Kong is based on mesenchymal stem cell (MSC) therapy at both preclinical and pilot clinical research stages. The assessment of therapy efficacy includes: behaviour (motor rod, water maze, gait analysis); pathological examination (haematoxylin and eosin stain, immuno-histochemistry); physiological factors (spikes, electrocardiogram [ECG]) and biochemical factors (biomarkers, gene expression). Several biomarkers are currently in clinical development.35–37

Experimental stem cell therapies currently use various cell types: embryonic, foetal, adult bone marrow, adipose tissue and induced pluripotent stem cells (iPS cells). Proposed mechanisms of action of adult stem cells in CNS injuries are: engraftment and cell differentiation or cell fusion, suppression of apoptosis, modulation of inflammation, paracrine/endocrine effects and enhancement of angiogenesis. Possible routes of administration include: systemic infusion, direct implantation and topical application. Stem cells therapies, however, are in early phase development and safety concerns must be addressed in clinical investigations.

An example of cell therapy for brain injury is the use of green fluorescent protein-mesenchymal cells (GFP-MSCs) in a rat model.38 The GFP-MSC cells migrate to the place of injury and impact on recovery at molecular and cellular level. Most importantly, this therapy achieved improvements in functional outcome assessed as performance in the Morris Water Maze experiment. MSC therefore holds considerable potential in the treatment of neurological disorders.39,40

There is a place for MSC-based therapies in axonal regeneration. However, experimental advances and better understanding have not yet converted into clinical practice. There is a need to develop better stem cell technology and to use this approach in combination with other agents, such as small molecules, which can enhance viability of the transplants as well as work in synergy with MSC for stimulation of endogenous repair mechanisms.