Multiple Systems Atrophy (M.S.A.) and Parkinson's Plus syndromes

Loss of GABAergic neurons of the direct output pathway of caudate-putamen results is a form of Parkinsonism, known as striato-nigral degeneration. While the mechanisms of striato-nigral degeneration are not known, excitotoxic injury has been implied in its mechanisms as well.

Stroke, Traumatic Brain Injury and Epilepsy

Current evidences suggest that excitotoxic mechanisms are involved in a variety of neurological disorders, including status epilepticus (SE), stroke and traumatic brain injury. These conditions lead to neuronal loss, sclerosis of brain tissue, synaptic reorganization and a variety of motor and cognitive dysfunctions, including epilepsy and memory impairments.

Status epilepticus commonly leads to the development of hippocampal sclerosis, a primary cause of temporal lobe epilepsy (TLE). SE results in neuronal injury and death in vulnerable brain areas, primarily in the hippocampus. Progressive neuronal loss, sclerosis, and accompanying plastic events (such as mossy fiber sprouting, increased neurogenesis in the dentate gyrus, alterations in neuropeptide expression) contribute to the establishing of network of pathologically interconnected neurons with increased seizure susceptibility.

In the hippocampus primary inhibitory system includes interneurons located in the hilus of the dentate gyrus (a.k.a polymorphic layer of the dentate gyrus). Interneurons use GABA as a main neurotransmitter and inhibit the activity of excitatory glutamatergic principal cells (pyramidal cells in CA1-CA3 and dentate granule cells), thus being referred to as inhibitory interneurons. Interneurons are highly vulnerable to the injury during precipitating insults. Both TLE in patients and animal models of TLE are characterized by relatively selective loss of GABAergic interneurons, which disinhibits principal cells.

Stroke leads to excitotoxic neuronal injury in the areas of insufficient blood supply due to ischemia or trombosis. Similarly to status epilepticus, patients develop sclerosis in the area of primary neuronal injury with clinical outcome depending on the location of the stroke (e.g. motor and cognitive deficits accompany striatal damage, while epilepsy is an outcome of hippocampal injury).Up to date no effective and mechanistically justified treatment of the consequences of stroke exists: patients are mostly treated symptomatically.

Brain trauma activates excitotoxic mechanisms in the projected area of impact with the outcome similar to stroke, which also depends on the location of the injury. Similarly to stroke, treatment of the trauma outcome is symptomatic.

Cell replacement as an approach for the treatment of excitotoxic neuronal injury. Following selective neuronal injury, targeted replacement of injured neurons seems a logical choice. For years attempts have been made to apply cell replacement approach to normalize brain functioning after excitotoxic insults. Replacing of the lost GABAergic neurons with functional GABAergic cells may be beneficial for treating of the consequences of excitotoxic injury.

Alzheimer's Disease

Alzheimer's Disease is the most frequent neurodegenerative disorder afflicting more than 4 million patients in the United States. The exact cause remains unknown but dysfunctional neurons.

Alzheimer's disease (AD) is a neurological disorder that affects neurons of hippocampus and cortex. Neuronal cell death is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD is a disease caused by loss of neurons points toward suppression of neuronal death as the most important therapeutic target. Nevertheless, the mechanisms for neuronal death in AD are still relatively unclear. Three known mutant genes cause familial AD (FAD): amyloid precursor protein, presenilin 1, and presenilin 2.

Current therapeutic approaches are related to manipulation of oxidative stress, hypoxia and inflammation in the affected areas of the CNS. These treatments have some effect on the early stages of disease and help to prevent its progression for some time. It is obvious that effective early detection and treatment requires innovative new approaches. New treatments may be based on gene therapy, cell therapy using stem cell derived neuron precursors or neurons and manipulation of transcription factors or signaling mechanisms.

Results of several preclinical animal experiments clearly demonstrate that transplantation of neuronal cells into the AD brain have a beneficiary effect and delay clinical symptoms of AD. Development of numerous techniques of obtaining stem cells from different sources, both embryonic and adult, opens the prospective to use these cells for replacement of lost neurons. Development of clinically relevant cell therapy for AD requires several critical steps including differentiation of stem cells into several types of neurons, optimal transplantation conditions and clear evidence that cell therapy will recover function of hippocampal and cortical neurons or delay the progression of disease.

Spinal Cord Injury

This inability of spinal cord to regenerate is due to lack of a natural way to replace lost neurons and establish intense functional connections between different neuronal populations after trauma. There is no effective therapy for promoting recovery of neurological function beyond the 8 hour period of acute spinal cord injury. Medical efforts are mostly directed towards preventing secondary complications and maximizing functionality of remaining neuronal systems but not stimulating regeneration and recovery of function. Reconnection of damaged circuitry and replacement of lost neurons are the main problems of neuronal regeneration and recovery of function after spinal cord injury. Complete recovery requires regeneration of both long and short distance axons and replacement of different types of neurons and glial cells.

Activation of long distance regeneration which will result in formation of functional synapses between descending fiber tract axons and local targets (motoneurons, interneurons) has been an ultimate goal for many research projects. Unfortunately, there is no effective technology to stimulate regeneration of descending axons in the injured spinal cord. Lack of progress in this area is likely related to the complexity of the problem. Adult spinal cord does not support but rather inhibits growth of regenerating axons and spinal cord cells do not express high levels of growth stimulatory factors such as neurotrophic factors. Despite the fact that small number of descending fibers has been demonstrated to regenerate when growth substrate and growth factors are provided, the problem of growth potential of adult neurons is still unsolved.

Numerous data demonstrate that transplantation of embryonic neural tissue, neural stem cells, embryonic stem cells or neurons at different stages of differentiation into the injured spinal cord stimulates formation of functional synapses between grafted and host neurons, help to "normalize" the excitability of specific spinal reflexes, prevent retrograde cell death, alter specific postinjury metabolic patterns and stimulate regeneration of long and short tract neurons. Development of clinically relevant cell therapy for spinal cord injury requires several critical steps including differentiation of stem cells into several types of neurons, optimal transplantation conditions and clear evidence that cell therapy will recover function of injured spinal cord.

Demyelinating Disorders (M.S, ALS)

Demyelination is a process of the destruction and loss of myelin from the axons and subsequent loss main axonal function, propagation of action potential. Both loss of oligodendrocytes and astrocytes is implicated.

The major demyelinating syndrome is multiple sclerosis (MS). Other demyelinating disorders include Amyotrophic Lateral Sclerosis and several types of immunological disorders of the central nervous system. Demyelinating diseases result in severe defects and ultimate loss of all motor function (voluntary and involuntary).

Amyotrophic lateral sclerosis (ALS) is a neurological disorder characterized by the selective degeneration of upper and lower motor neurons. Several mechanisms have been proposed to account for the progressive motor neuron death in ALS. These include oxidative stress, neurofilament damage, mitochondrial abnormalities, glutamate-mediated excitotoxicity, altered response to hypoxia and gene regulation based defects. Current therapeutic approaches are related to manipulation of oxidative stress, hypoxia and inflammation in the affected areas of the CNS. These treatments have some effect on the early stages of disease and help to prevent its progression for some time. It is obvious that effective early detection and treatment requires innovative new approaches. New treatments may be based on gene therapy, cell therapy using stem cell derived motor neuron precursors or motor neurons and manipulation of transcription factors or signaling mechanisms.