PDE10A inhibition as a possible treatment of TS

A paper “A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders” was recently published:

The inhibition of phosphodiesterase 10A (PDE10A) is a novel approach to the treatment of basal ganglia disorders, including TS.

PDE10A is a member of the phosphodiesterase superfamily of enzymes that regulate through the metabolic inactivation of the intracellular second messengers cAMP and cGMP. PDE10A is unique in that it is expressed at high levels only in MSNs and to a very limited extent elsewhere in the brain and body.

In MSNs, PDE10A regulates both cAMP and cGMP signaling, although the cyclic nucleotide pools under the control of the enzyme are not directly or exclusively linked to dopamine signaling.

Despite its expression in all MSNs, PDE10A inhibition results in the preferential activation of the indirect striatal output pathway, which, in some preclinical assessments, is evident as behavioral suppression similar to that caused by D2 antagonists.

Nonetheless, PDE10A inhibitors have a unique profile, possibly in part due to their coincident activation of the direct pathway and the indirect pathway. This was captured in a study of the PDE10A inhibitor MP-10 in non-human primates, where D2 antagonism disrupted the motor expression of behavior, but PDE10A inhibition appeared to have suppressed the initiation of task execution. (R1)

What is PDE10A?

It’s an enzyme that hydrolyzes cyclic AMP to 5’AMP and cyclic GMP to 5’GMP using water molecule. This stops propagation of the intracellular signals that are carried by cAMP and cGMP.

PDE10A uses divalent metal cations as a cofactor, binding preferentially Zinc2+ by Site 1, and Mg2+ or Mn2+ by Site 2. (R2)

PDE10A had an 11-fold higher affinity for cGMP than cAMP, and cAMP efficiently inhibited cGMP phosphodiesterase activity (R3)

Health implications

Genetic mutations in the gene PDE10A lead to “Dyskinesia, limb and orofacial, infantile-onset (IOLOD)” and “Striatal degeneration, autosomal dominant 2 (ADSD2)”.

Interesting, that the first disorder is described more like insufficient activation of movements, while the second disorder is hyperkinesis.

PDE10A inhibitors are evaluated as a treatment for Schizophrenia:

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. (R4)

PDE10A is a unique signaling molecule in being highly expressed in only a single neuronal population and in having a singular molecular signaling role.

This localization prompted an intensive effort to determine the role of PDE10A in regulating striatal function and to investigate the potential therapeutic utilities of PDE10A inhibitors (R5)

Inhibitors of PDE3 are used for the treatment of heart failure (milrinone), PDE4 inhibitors are used for treating inflammatory conditions such as COPD (roflumilast) and psoriatic arthritis (apremilast), and PDE5 inhibitors are used for erectile dysfunction (sildenafil, tadalafil, and vardenafil) and pulmonary hypertension (sildenafil).

With the proven track record of identifying drugs that inhibit PDEs, there was significant excitement in the pharmaceutical world when PDE10A was identified as a potential new target in 1999. (R5)

Effects of PDE10A inhibition

In clinical studies to date, PDE10A inhibitors have generally been found to be safe and well-tolerated at doses yielding exposures in the range targeted for efficacy (Tsai et al., 2016).

Significantly, PDE10A inhibitors were found to be psychoactive in the targeted exposure ranges, producing a state characterized as “awake sedation” or “conscious sedation,” as discussed at a NIMH-sponsored workshop on PDE10A held January 25, 2013 at the NIH Neuroscience Center in Rockville, MD, USA.

At higher exposures, PDE10A inhibitors were found to induce sporadic dystonia, particularly of the tongue, head, and neck. This motor side effect is consistent with the compounds modulating basal ganglia circuitry, albeit in a maladaptive fashion. (R5)

Thoughts

It looks like PDEs’s main role is to deactivate cAMP and cGMP signal transduction by rerouting molecules into 5' AMP and 5' GMP.

Without PDE’s work, the signal would propagate and activate downstream cascades.

Paper (R6) has a nice chart showing that both cAMP and cGMP has downstream inhibition of GSK3b, so when PDE is (over)active the deactivated cAMP is not able to lead to GSK3b inhibition, which would be important.

Another consideration is the balance between cAMP and cGMP:

cAMP abundance coupled to PKA signaling is critical to modulate assembly / disassembly / priming / recycling of neurotransmitter vesicles and, consequently, for synaptic transmission and plasticity events.

cGMP signaling can be transmitted through cyclic nucleotide-gated or hyperpolarization-activated cyclic nucleotide-gated ion channels. Furthermore, pharmacological inhibition of soluble GC or PKG slowed down the rate of recycling as well as endocytosis of synaptic vesicles. Indeed, the NO/cGMP/PKG pathway is known to modulate transmitter release and long-term changes of synaptic activity in various brain regions.

Overall, the balance between cAMP and cGMP levels is considered to be essential for shaping neuronal circuits (R6).

The question is - what is the problem in the first place:

Are PDEs overactive OR the levels of cAMP/cGMP are too low to deliver the message downstream OR the downstream cascade is abnormally weak for some reason?