Dr Yona Goldshmit at the Centre for Neuroscience at the University of Melbourne was awarded the SpinalCure Australia Fellowship for $100,000 over a three-year period.

May 2007 - We have received a progress report from Dr Yona Goldshmit of the Neural Regeneration Laboratory, Centre for Neuroscience at the University of Melbourne. She is the recipient of the SpinalCure Australia Senior Fellowship (2006-2008). Yona’s research involves blocking the action of a molecule named EphA4 which creates a scar or lesion. This forms after traumatic injury on the damaged spinal cord.

The full lay summary of Yona’s project follows. We are sure many of our supporters will find it interesting reading.
It indicates that great progress is being made to reduce the effects of spinal cord injury by taking immediate action after the injury occurs. The report also confirms the findings of many scientists, that exercise taken in conjunction with other therapies has a beneficial influence on spinal cord injury sufferers.

Inhibition of EphA4 results in axonal regeneration after spinal cord injury

In our previous studies, we have demonstrated that adult mice lacking EphA4, exhibit extensive axonal regeneration and functional recovery after spinal cord hemisection. In normal mice, EphA4 expression was upregulated after spinal cord injury, especially on astrocytic cells, which create the glial scar at the site of the injury. In the mice lacking EphA4 the glial scar was greatly reduced. Blocking of EphA4 may thus lead to potential therapeutic benefit. To assess this potential, two different blockers of EphA4 were examined for their ability to promote axonal regeneration and improve functional outcome following spinal cord injury in normal mice. One week of administration of an EphA4 blocker enhanced axonal regrowth towards the lesion site. It was, however, insufficient to promote regeneration through the lesion site. Therefore, longer administration time was examined. Two week administration of the EphA4 blockers led to axonal regeneration through the lesion site and improved functional recovery. A method of analysis of the paralysed hindlimb joint movement was developed and set up in the lab. Analysis of gait, known as kinematic analysis, is a sensitive assessment tool that is able to differentiate subtle changes in the execution of movements, which are undetectable by visual observation alone, in a highly quantitative and objective manner. In mice treated with EphA4 blockers, the kinematic analysis showed that the hip joint started to approximate normal movement, although the range was diminished. The knee joint showed some movement but the timing was altered, with a shorter stance phase while untreated mice showed almost no knee movement. Movement of the ankle joint of treated mice was small, however in untreated mice the effect at the ankle was very variable, ranging from fully flexed (spastic) to dragging. In addition, we have studies the role of exercise as a therapeutic strategy after spinal cord injury. As a result of treadmill-training, the exercised mice showed decreased muscle atrophy, increased axonal regrowth and collateral sprouting upstream to the lesion site, with maintenance of synapses on motor neurons. However, there was no axonal regeneration into or across the lesion site indicating that the improved behaviour was, at least in part, due to enhanced neural activity above the lesion site.

Summary 2008

In our previous studies, we have demonstrated that adult mice lacking EphA4 exhibit extensive axonal regeneration and functional recovery after spinal cord hemisection. In normal mice EphA4 expression was upregulated after spinal cord injury, especially on astrocytic cells, which create the glial scar at the site of the injury. In the mice lacking Epha4 the glial scar was greatly reduced. Blocking of EphA4 may thus lead to potential therapeutic benefit. To assess this potential, two different blockers of EphA4 were examined for their ability to promote axonal regeneration and improve functional outcome following spinal cord injury in normal mice. Two week administration of the EphA4 blockers led to axonal regeneration through the lesion site and improved functional recovery. This year we further examined regeneration through the lesion site using 6 different Epha4 blocking or control compounds in double blinded experiments. Two of the compounds were the effective at blocking the inhibitory effects of EphA4 and promoting axonal regeneration and functional recovery. However, the ephrin proteins are difficult to produce in large quantities. Their stability in plasma and ability to access the site of damage may be limited, therefore small peptide molecules that were designed to block the interaction between EphA4 and ephrins were produced. During the last year we started to examine different peptides in experiments on cultured astrocytes and neurons. Results show some efficiency in blocking EphA4 effects but they have to be further characterised.
In addition, we continued to characterize behavioral and anatomical differences as a result of treadmill training after spinal cord injury and showed decreased muscle atrophy and increased neuronal regrowth towards the injury site. However, there was no regeneration into or across the lesion site. This indicated that the improved behaviour of the mice may have been, at least in part, due to enhanced neural activity above the lesion site.
We also examined Lysophosphatidic Acid (LPA) receptor expression after spinal cord injury. LPA is known to play a role during neural development and is released into tissues following injury in the adult, however little is known about the expression of LPA receptors in the adult nervous system and the role that LPA may play in the regulation of neural regeneration. We examined expression of the LPA receptors LPA1, LPA2 and LPA3 in intact, uninjured spinal cord tissue as well as these same tissues following spinal cord injury. LPA2 receptor was upregulated on astrocytes and LPA3 receptor was upregulated on motor neurons after spinal cord injury, while LPA1 receptor expression remained unchanged.

Yona Goldshmit, PhD