New therapeutic approaches for peripheral compression neuropathies

Chronic peripheral nerve compression injuries, a distinct type of neuropathies, are characterized by paresthesia, pain, numbness and tingling. These neuropathies are caused by the entrapment or the compression of a nerve or its root. Some of the common compression neuropathies include carpal tunnel syndrome, cubital tunnel syndrome or meralgia paraesthetica, sciatica and low back pain. Current treatment options include corticosteroids, muscle relaxants and non-steroidal anti-inflammatory drugs that can be supplemented with physical and massage therapies. These therapeutic approaches are associated with several limitations and are regularly followed by a surgery to release the nerve from the compression injury. Unfortunately, these surgeries are not effective and moreover, surgeries often result in detrimental outcomes such as scar complication, muscle weakness and pillar pain. Given the facts on the growing number of nerve injuries and the inefficient current treatments, there is a clear need for new and innovative therapeutic strategies. Thus, the aim of the present research work is to develop a compression injury model with a defined setting (i.e., compression depth and time) and to investigate various therapeutic strategies that may pave the way for the novel and effective therapeutic developments.
Due to lack of consistent nerve compression model with the established sensory and motor pathologies in the literature, the first objective of the present thesis work is set to establish a model that would mirror chronic peripheral nerve compression injury in terms of function and anatomy. The first manuscript is describing that attempt of a reproducible model that was achieved by the entrapment of the rat sciatic nerve using a modified hemostatic clip. This chronic injury model is giving functional and histomorphological markers for the evaluation the impairment caused by different levels of compression.
Chronic peripheral nerve compression injuries, a distinct type of neuropathies, are characterized by paresthesia, pain, numbness and tingling. These neuropathies are caused by the entrapment or the compression of a nerve or its root. Some of the common compression neuropathies include carpal tunnel syndrome, cubital tunnel syndrome or meralgia paraesthetica, sciatica and low back pain. Current treatment options include corticosteroids, muscle relaxants and non-steroidal anti-inflammatory drugs that can be supplemented with physical and massage therapies. These therapeutic approaches are associated with several limitations and are regularly followed by a surgery to release the nerve from the compression injury. Unfortunately, these surgeries are not effective and moreover, surgeries often result in detrimental outcomes such as scar complication, muscle weakness and pillar pain. Given the facts on the growing number of nerve injuries and the inefficient current treatments, there is a clear need for new and innovative therapeutic strategies. Thus, the aim of the present research work is to develop a compression injury model with a defined setting (i.e., compression depth and time) and to investigate various therapeutic strategies that may pave the way for the novel and effective therapeutic developments.
Due to lack of consistent nerve compression model with the established sensory and motor pathologies in the literature, the first objective of the present thesis work is set to establish a model that would mirror chronic peripheral nerve compression injury in terms of function and anatomy. Thus, the first manuscript describes anatomical and functional changes in response to the controlled chronic nerve compression that would enable pharmaceutical drug targeting and development. For this, we first prepared custom made surgical instrument that leaves a vascular clip with a predefined lumen volume (i.e., 400μm, 250μm, 100μm and 0μm). Animals were randomized into 4 groups (n=6) and the left sciatic nerve were exposed and compressed at 10mm proximal from the nerve branching resulting in controlled degree nerve damage. The titanium compression clip was left on the sciatic nerve over 6 weeks. Post-operatively, anatomical (histomorphology), sensory and motor functions (electrophysiology) were analyzed. Resulting data and observations revealed the compression-depth dependent sensory and motor pathologies. Further, quantitative measurements revealed compression depth dependent decline in myelin, myelin sheath thickness, axonal surface and muscle weight. Sensory and motor functional dynamics were evident in response to differential injury severity. In short, such controlled compression nerve injury model would enable the investigation of basic mechanisms and repair avenues.
In the second manuscript, we explored the immunomodulation-based treatment strategy, for repair and regeneration of chronic nerve compression injuries. Within this context, three molecules, i.e., Cyclosporine, FK506 and Rapamycin, were evaluated in an in vitro model involving a serum-free culture of embryonic dorsal root ganglia (DRG) followed by in an in vivo model of chronic sciatic nerve compression. Axonal outgrowth analysis confirmed the growth promoting properties of all 3 different drug molecules, which are comparable with NGF. Drug treated animals exhibited the ability to prevent from injury induced neuromuscular degeneration and to restore the function. Among all the drug molecules, cyclosporine appeared to be more effective to support animals as evidenced by significantly preserved structure and function. Further studies are required to assess the effects of sustained local release of cyclosporine for treating the chronic nerve injuries.
In the search for new therapeutic strategies to treat chronic peripheral nerve compressions, two neuroactive synthetic molecules based on the natural paecilomycine A (PSM) have attracted attention. Thus, the third manuscript covers the neurotrophic and neuroprotective potential of PSM in vitro using embryonic dorsal root ganglia (DRG) and further translated into a rat model of chronic nerve compression. In vitro analysis of neuronal survival and axonal outgrowth in response to paecilomycine diverted synthetic molecule 1 (PSM1) and 2 (PSM2) at various concentrations (10µM and 100µM) suggested their neurotrophic capacity that is comparable to standard NGF. Furthermore, low doses of the molecules, systemically administered, appeared to protect the neuromuscular structures and function. PSM1 appeared to have a stronger effect than PSM2 in terms of neuroprotection as evidenced by significantly improved anatomy and behavioral recovery. Together these findings and observations indicate neurotrophic and neuroprotective activity for both molecules while the former is being more neurotrophic and the other one is being more neuroprotective.
In conclusion, the present thesis work produced relevant new knowledge and data in the field of neuropathies paving the way for innovative treatment options for peripheral compression neuropathies.