In response to stress, cells stimulate synthesis and mobilization of cytoprotective proteins, such as heat shock proteins (HSP). This process is collectively termed as the heat shock response (HSR) and ensures that cells are protected from cellular damage under stress.
Arimoclomol is a hydroxylamine derivative that functions as a co-inducer of heat shock proteins (HSP), specifically in cells undergoing stress. The elevated HSP expression is partly due to stabilization of the active phosphorylated trimer of heat shock factor 1 (HSF-1) and prolonged binding of HSF-1 to heat shock elements (HSE).
Neuroprotective effects of arimoclomol
Arimoclomol displays neuroprotective effects in a few neurodegenerative disease models, such as amyotrophic lateral sclerosis (ALS). In superoxide dismutase 1 (SOD1) G93A mouse model of ALS, treatment with arimoclomol resulted in delayed disease onset, enhanced neuromuscular activity and increased survival of motor neurons. Furthermore, these mice presented with reduced protein aggregates positive for ubiquitin in motor neurons.
Arimoclomol also acts on non-neuronal cells, such as astroglia and muscles, to increase HSP expression. In the SOD1 G93A mouse model, arimoclomol enhances muscle innervation prior to eliciting central effects on the heat shock response (HSR) in the spinal cord.
Arimoclomol also demonstrated efficacy in a mouse model of spinal and bulbar muscular atrophy (SBMA). Administration of arimoclomol in these mice resulted in increased motor neuron survival and increased HSP expression.
Overall, these findings support therapeutic potential for arimoclomol in treating ALS patients. Phase II clinical trials demonstrated good safety and tolerance to arimoclomol in ALS patients. Phase II/III trial is currently underway in SOD1-positive fALS (familial amyotrophic lateral sclerosis) patients.
Effect of Arimoclomol on apoptosis
Increased HSPs result in anti-apoptotic activity, mediated by various mechanisms. Motor neurons treated with arimoclomol become more resistant to pro-apoptotic stimuli. This effect is thought to be mediated by decreased caspase-3 activation that is required for the apoptotic cascade.
Other potential activities of arimoclomol
An analog of arimoclomol, bimoclomol, has been shown to target the cell membrane for enhancing HSP expression. This is mediated by increasing the fluidity of negatively charged membrane lipids. Furthermore, another analog of arimoclomol, BGP-15, inhibits disintegration of membrane lipid rafts in response to heat-induced stress. It is therefore postulated that arimoclomol may also act on the cell membrane to induce HSR.
Similarly, as BGP-15 can reduce the formation of reactive oxygen species, arimoclomol may also have anti-oxidant properties that contribute to the survival benefits seen in ALS models.