Dystonia Pathophysiology: A Critical Review

Burbaud, Pierre

doi:10.5772/30295

Cited by 2 publications

(2 citation statements)

References 182 publications

(232 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several reports have suggested that overactivity in the direct pathway is involved in the production of dystonia (Burbaud, 2012; Janavs and Aminoff, 1998); thus, faster off-rate PDE10A inhibitors may also have an improved pharmacological profile for tolerability.…”

Section: Discussionmentioning

confidence: 99%

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Suzuki

Harada

Suzuki

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D 1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D 2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Suzuki

Harada

Suzuki

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…In fact, a cataleptic response induced by activation of the indirect pathway by haloperidol was canceled by excessive activation of the direct pathway by a D 1 receptor agonist SKF82958 in rats . Moreover, several reports have suggested that excessive activation of the direct pathway MSNs is involved in the production of dystonia, one of the major clinical features of HD (Janavs and Aminoff, 1998;Louis et al, 1999;Burbaud, 2012). It is not known whether the indirect pathway MSN-biased activation pattern by TAK-063 would translate to therapeutic benefit in humans.…”

Section: Tablementioning

confidence: 99%

TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington’s Disease

Harada¹,

Suzuki²,

Kimura³

2016

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Huntington's disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling. Compared with other PDE10A inhibitors, a novel PDE10A inhibitor 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063) showed comparable activation of the indirect pathway MSNs, whereas it produced partial activation of the direct pathway MSNs by its faster off-rate property. In this study, we report the effects of TAK-063 on striatal neurodegeneration and behavioral deficits in the R6/2 mouse model of HD. TAK-063 at 0.5 or 5 mg/kg/day was orally administrated from 4.5-5 to 12 weeks of age, and the effects of TAK-063 were characterized over this period. Repeated treatment with TAK-063 suppressed the reduction of brain-derived neurotrophic factor levels, prevented striatal neurodegeneration, and suppressed increase in seizure frequency, but did not prevent the suppression of body weight gain. As for motor deficits, TAK-063 suppressed the development of clasping behavior and motor dysfunctions, including decreased motor activity in the open field, but did not improve the impairment in motor coordination on the rotarod. Regarding cognitive functions, TAK-063 improved deficits in procedural learning, but was ineffective for deficits in contextual memory. These results suggest that TAK-063 reduces striatal neurodegeneration and ameliorates behavioral deficits in R6/2 mice.

show abstract

Dystonia Pathophysiology: A Critical Review

Cited by 2 publications

References 182 publications

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington’s Disease

Contact Info

Product

Resources

About