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Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1.

Notartomaso S, Zappulla C, Biagioni F, Cannella M, Bucci D, Mascio G, Scarselli P, Fazio F, Weisz F, Lionetto L, Simmaco M, Gradini R, Battaglia G, Signore M, Puliti A, Nicoletti F - Mol Brain (2013)

Bottom Line: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells.A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug.The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: I,R,C,C,S, Neuromed, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.

ABSTRACT

Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.

Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.

Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

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Pharmacological enhancement of mGlu1 receptors causes a prolonged symptomatic benefit in SCA1 mice. Motor performance on the rotarod in SCA1 mice with severe motor impairment at different times following a single injection of vehicle or Ro0711401 is shown in (A), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding values at time 0; Two-way ANOVA for repeated measures + Fisher’s LSD; F(7,35) = 2.48, F(1,10) = 21.003, and F(7,35) = 2.321 for time, treatment, and time x treatment, respectively. Motor performance in SCA1 mice with mild impairment treated daily with Ro0711401 is shown in (B), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding pre-treatment values; Two-way ANOVA for repeated measures + Fisher’s LSD; F(5,15) = 4.248, F(1,11) = 37.408 and F(5,15) = 6.078 for time, treatment and time x treatment, respectively. The lack of motor effect of single injection of Ro0711401 in wild-type littermates is shown in (C), where values are means ± S.E.M. of 4 mice per group.
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Figure 4: Pharmacological enhancement of mGlu1 receptors causes a prolonged symptomatic benefit in SCA1 mice. Motor performance on the rotarod in SCA1 mice with severe motor impairment at different times following a single injection of vehicle or Ro0711401 is shown in (A), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding values at time 0; Two-way ANOVA for repeated measures + Fisher’s LSD; F(7,35) = 2.48, F(1,10) = 21.003, and F(7,35) = 2.321 for time, treatment, and time x treatment, respectively. Motor performance in SCA1 mice with mild impairment treated daily with Ro0711401 is shown in (B), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding pre-treatment values; Two-way ANOVA for repeated measures + Fisher’s LSD; F(5,15) = 4.248, F(1,11) = 37.408 and F(5,15) = 6.078 for time, treatment and time x treatment, respectively. The lack of motor effect of single injection of Ro0711401 in wild-type littermates is shown in (C), where values are means ± S.E.M. of 4 mice per group.

Mentions: We next examined the temporal profile of response to a single injection of Ro0711401 in SCA1 mice by assessing motor performance on the rotarod every day for 6 days. Surprisingly, a single administration of Ro0711401 caused a long-lasting improvement in motor performance, which was maintained to the same extent at least for 6 days (Figure 4A). Again, the drug had no effect in wild-type littermates (Figure 4C). We also tested motor performance in response to daily administrations of Ro0711401 (10 mg/kg, s.c., for 6 days) showing no development of tolerance to the motor-improving effect of the drug (Figure 4B).


Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1.

Notartomaso S, Zappulla C, Biagioni F, Cannella M, Bucci D, Mascio G, Scarselli P, Fazio F, Weisz F, Lionetto L, Simmaco M, Gradini R, Battaglia G, Signore M, Puliti A, Nicoletti F - Mol Brain (2013)

Pharmacological enhancement of mGlu1 receptors causes a prolonged symptomatic benefit in SCA1 mice. Motor performance on the rotarod in SCA1 mice with severe motor impairment at different times following a single injection of vehicle or Ro0711401 is shown in (A), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding values at time 0; Two-way ANOVA for repeated measures + Fisher’s LSD; F(7,35) = 2.48, F(1,10) = 21.003, and F(7,35) = 2.321 for time, treatment, and time x treatment, respectively. Motor performance in SCA1 mice with mild impairment treated daily with Ro0711401 is shown in (B), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding pre-treatment values; Two-way ANOVA for repeated measures + Fisher’s LSD; F(5,15) = 4.248, F(1,11) = 37.408 and F(5,15) = 6.078 for time, treatment and time x treatment, respectively. The lack of motor effect of single injection of Ro0711401 in wild-type littermates is shown in (C), where values are means ± S.E.M. of 4 mice per group.
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Figure 4: Pharmacological enhancement of mGlu1 receptors causes a prolonged symptomatic benefit in SCA1 mice. Motor performance on the rotarod in SCA1 mice with severe motor impairment at different times following a single injection of vehicle or Ro0711401 is shown in (A), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding values at time 0; Two-way ANOVA for repeated measures + Fisher’s LSD; F(7,35) = 2.48, F(1,10) = 21.003, and F(7,35) = 2.321 for time, treatment, and time x treatment, respectively. Motor performance in SCA1 mice with mild impairment treated daily with Ro0711401 is shown in (B), where values are means ± S.E.M. of 6 mice per group. *p < 0.05 vs. the corresponding pre-treatment values; Two-way ANOVA for repeated measures + Fisher’s LSD; F(5,15) = 4.248, F(1,11) = 37.408 and F(5,15) = 6.078 for time, treatment and time x treatment, respectively. The lack of motor effect of single injection of Ro0711401 in wild-type littermates is shown in (C), where values are means ± S.E.M. of 4 mice per group.
Mentions: We next examined the temporal profile of response to a single injection of Ro0711401 in SCA1 mice by assessing motor performance on the rotarod every day for 6 days. Surprisingly, a single administration of Ro0711401 caused a long-lasting improvement in motor performance, which was maintained to the same extent at least for 6 days (Figure 4A). Again, the drug had no effect in wild-type littermates (Figure 4C). We also tested motor performance in response to daily administrations of Ro0711401 (10 mg/kg, s.c., for 6 days) showing no development of tolerance to the motor-improving effect of the drug (Figure 4B).

Bottom Line: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells.A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug.The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: I,R,C,C,S, Neuromed, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.

ABSTRACT

Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.

Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.

Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

Show MeSH
Related in: MedlinePlus