semapimod and Nerve-Degeneration

Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons in the substantia nigra. Neuroinflammatory processes have been shown to be a key component of this neurodegeneration and, as such, small molecule compounds which inhibit these inflammatory events are a critical research focus.. CNI-1493 is an anti-inflammatory compound that strongly inhibits macrophages and also stimulates the cholinergic anti-inflammatory pathway. We have examined whether CNI-1493 has a neuroprotective effect in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.. CNI-1493 (8 mg/kg i.p.) or placebo administration was started 1 day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57/Bl6 mice - either treated with CNI-1493 or with placebo - were injected intraperitoneally 4 times at 2-hour intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or 7 days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis.. Administration of CNI-1493 markedly protected tyrosine hydroxylase-positive substantia nigra neurons against MPTP neurotoxicity. CNI-1493 treatment in the MPTP model was also accompanied by a profound reduction of activated microglia within the substantia nigra, as measured by ionized calcium-binding adapter molecule-1 staining.. These findings support that CNI-1493 could reduce the MPTP-induced toxicity likely by inhibition of neuroinflammatory responses. The neuroprotective effect of CNI-1493 suggests that CNI-1493 might be a valuable neuroprotective candidate in the future treatment of PD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dopaminergic Neurons; Hydrazones; Inflammation; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Parkinson Disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective loss of motor neurons. Stress activated protein kinases (SAPK) have been suggested to play a role in the pathogenesis of ALS. We studied the relevance of p38 MAPK for motor neuron degeneration in the mutant SOD1 mouse. Increased levels of phospho-p38 MAPK were present in the motor neurons and microglia of the ventral spinal cord. The p38 MAPK-inhibitor, SB203580, completely inhibited mutant SOD1-induced apoptosis of motor neurons and blocked LPS-induced activation of microglia. Semapimod, a p38 MAPK inhibitor suitable for clinical use, prolonged survival of mutant SOD1 mice to a limited extent, but largely protected motor neurons and proximal axons from mutant SOD1-induced degeneration. Our data confirm the abnormal activation of p38 MAPK in mutant SOD1 mice and the involvement of p38 MAPK in mutant SOD1-induced motor neuron death. We demonstrate the effect of p38 MAPK inhibition on survival of mutant SOD1 mice and reveal a dissociation between the effect on survival of motor neurons and that on survival of the animal, the latter likely depending on the integrity of the entire motor axon.

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents, Non-Steroidal; Axons; Cell Death; Cell Survival; Enzyme Activation; Enzyme Inhibitors; Hydrazones; Imidazoles; Mice; Mice, Transgenic; Motor Neurons; Mutation; Nerve Degeneration; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Pyridines; Superoxide Dismutase