calpain and Movement-Disorders

Postsynaptic density protein-95 (PSD-95) is a multidomain protein critical to the assembly of signaling complexes at excitatory synapses, required for neuronal survival and function. However, calpain-processing challenges PSD-95 function after overactivation of excitatory glutamate receptors (excitotoxicity) in stroke, a leading cause of death, disability and dementia in need of efficient pharmacological treatments. A promising strategy is neuroprotection of the infarct penumbra, a potentially recoverable area, by promotion of survival signaling. Interference of PSD-95 processing induced by excitotoxicity might thus be a therapeutic target for stroke and other excitotoxicity-associated pathologies.

Topics: Animals; Brain Ischemia; Calpain; Cell Survival; Cell-Penetrating Peptides; Cells, Cultured; Disease Models, Animal; Disks Large Homolog 4 Protein; Down-Regulation; Excitatory Amino Acid Agonists; HEK293 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Movement Disorders; N-Methylaspartate; Neurons; Neuroprotection; Stroke

Although calpain (calcium-activated cysteine protease) inhibition represents a rational therapeutic target for spinal cord injury (SCI), few studies have reported improved functional outcomes with post-injury administration of calpain inhibitors. This reflects the weak potency and limited aqueous solubility of current calpain inhibitors. Previously, we demonstrated that intraspinal microinjection of the calpain inhibitor MDL28170 resulted in greater inhibition of calpain activity as compared to systemic administration of the same compound. In the present study, we evaluated the ability of intraspinal MDL28170 microinjection to spare spinal tissue and locomotor dysfunction following SCI. Contusion SCI was produced in female Long-Evans rats using the Infinite Horizon impactor at the 200-kdyn force setting. Open-field locomotion was evaluated until 6 weeks post-injury. Histological assessment of tissue sparing was performed at 6 weeks after SCI. The results demonstrate that MDL28170, administered with a single post-injury intraspinal microinjection (50 nmoles), significantly improves both locomotor function and pathological outcome measures following SCI.

Topics: Animals; Calpain; Cysteine Proteinase Inhibitors; Dipeptides; Disease Models, Animal; Female; Microinjections; Motor Activity; Movement Disorders; Nerve Fibers, Myelinated; Rats; Rats, Long-Evans; Spinal Cord; Spinal Cord Injuries; Treatment Outcome