The Muscle Relaxant Dantrolene is Neuroprotective in a Mouse

Model of HD

 

Dr. Ilya Bezprozvanny and colleagues from the University of Texas Southwestern Medical Center have reported that dantrolene, a muscle relaxant used to treat malignant hypothermia and malignant neuroleptic syndrome, is neuroprotective in the YAC128 mouse model of HD.

 

Previous research in the Bezprozvanny lab has shown that calcium signaling is deranged in the medium spiny neurons (MSNs) of the YAC128 HD mouse model and that this derangement sensitizes the cells to excitotoxicty induced by glutamate, leading to apoptosis (cell death).

 

Dr. Bexprozvanny has devoted years to testing and confirming the calcium signaling hypothesis and investigating the pathways by which the derangement occurs.   In previous research he has found three.

 

In a study pcovered earlier this year, he and his colleagues found that the store operated calcium (SOC) pathway is heightened in the HD cells as compared to normal cells.  He had previously found that mutant huntingtin specifically binds to and activates the C-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1), an intracellular Ca(2+) release channel.  This could cause calcium to be released from the ER which would then activate the SOC pathway to replace it.  Over time, calcium would build up in the cell and cause stress.

 

In addition to these two pathways, research by Dr. Bezprovzanny and others has shown that increased Ca2+ influx via extrasynaptic NR2B subunit of N-methyl-D-aspartate receptor (NMDAR) plays an important role in excitotoxic cell death of HD MSN neurons.

 

Ca2+-induced Ca2+ release is triggered by the ryanodine receptors (RyanR) which in turn amplifies the release of calcium by the other pathways.  The researchers hypothesized that a RyanR inhibitor could be neuroprotective and chose dantolene, a known RyanR inhibitor and a calcium signaling stabilizer, for research.

 

In this study*, the researchers first exposed YAC128 and normal mouse MSNs to caffeine, a RyanR agonist (inducer) and glutamate.  Intracellular levels in both the HD and normal mouse MSNs were elevated but the levels were significantly higher in the HD model cells.  These data demonstrate that calcium induced calcium release (CICR) from RyanR-gated stores is significantly increased in YAC128 MSNs compared to normal MSNs when challenged with glutamate.

 

YAC128 and normal MSNs were then treated with a high concentrate of glutamate previously shown to induce apoptosis in a cell model of HD.  Apoptosis occurred in cultures of both types of cells but at higher percentages in the YAC128 cells.  YAC128 neurons that had been pretreated with dantrolene were rescued in a dose dependent manner.  Interestingly, apoptosis was not reduced in the normal MSNs.

 

Dantrolene was fed twice weekly to the YAC128 mice from the age of 2 to 11.5 months.   As the mice age, motor ability decreases, but the dantrolene resulted in improved performance compared to the control group, as measured by beam-walking and gait-walking assays.  Further, the dantrolene significantly reduced the loss of NeuN-positive striatal neurons. Neu-N is a nuclear-specific marker of mature neurons.

 

The researchers hypothesize that dantrolene exerts its neuroprotective effects by inhibiting RyanR which then inhibits the CICR mechanism which amplifies the signal from other calcium sources such as InsP3R1 and the NMDARs, described above.  With multiple sources all blunted at the same time, significant neuroprotection can be achieved.  There is also evidence from other researchers that dantrolene can inhibit the SOC pathway.

 

Dantrolene produces a number of significant side effects and is not likely to be suitable for long term use.  However, given the significant results demonstrated by this study, researchers will almost certainly be interested in discovering and/or developing other drugs which inhibit the ryanodine receptor.

 

References:

 

Ilya Bezprozvanny. “Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington's Disease and Spinocerebellar Ataxias.” Neurochemical Research 2011 Jul;36(7):1186-97.

 

Jun Wu, Hsin-Pei Shih, Vladimir Vigont, Lori Hrdlicka, Len Diggins, Carol Singh, Matt Mahoney, Richard Chesworth, Gideon Shapiro, Olga Zimina, Xuesong Chen, Qingqing Wu, Lyubov Glushankova, Michael Ahlijanian, Gerhard Koenig, Galina N. Mozhayeva, Elena Kaznacheyeva and Ilya Bezprozvanny. “Neuronal Store-Operated Calcium Entry Pathway as a Novel Therapeutic Target for Huntington's Disease Treatment.” Chemistry and Biology 24 Volume 18, Issue 6, June 2011, Pages 777-793.

 

*Xi Chen, Jun Wu, Svetlana Lvovskaya, Emily Herndon, Charlene Supnet and Ilya Bezprozvanny.  “Dantrolene is neuroprotective in Huntingtons disease transgenic mouse model.” Molecular Neurodegeneration. 2011, 6:81.

 

- Marsha L. Miller, Ph.D., November 28, 2011