Have you ever wondered how will be your life if you were just a little bit smarter? I’m not referring to be Stephen Hawkings, but just having some extra push. One would be able, for example, to be more efficient, or to be more creative, more imaginative or be an encyclopedia of knowledge. What if you could do more things and faster just by taking a pill, just as the protagonist of “Limitless”? He is a writer in a drought stage that, by taking a new nootropic or cognitive enhancer, is converted into a prolific writer and business shark.
Imagine this magic pill. Just as simple as taking the vitamin supplement. And, of course, no secondary effects! Wouldn’t it be marvelous?
We would feel capable of anything and everything. However, there are people that are struggling for this pill, but with the goal of having the same capacities you and me have right now. I am referring to all the people that are suffering from neurodegenerative diseases such as Alzheimer, Parkinson or psychiatric diseases like Schizophrenia or Bipolar Disorder, who are witnesses of their cognition decline as the illness stablishes.
Doing the same fantastic exercise as previously, imagine now that you cannot understand the information you are reading in this exact moment. Imagine that you will not retain it, nor remember it after two minutes. How would you feel? You would not be able to perform basic day-to-day activities. You would be incapable of working. Imagine this. Wouldn’t it be a nightmare?
Is in this endless nightmare where millions of people live. And there is no magic pill in real life to wake up from it.
Among this huge population, schizophrenia patients represent a miscellaneous group, with diverse symptoms. Cognitive ones represent the core of the disease, and are the first ones to appear. They affect among the 80% of schizophrenia patients, and hinder understanding, retention and memory. There is no current treatment for cognitive deficit, despite the fact that several companies are pursuing it since decades ago.
And if there is such an intense research, why there is no current treatment? Basically, because every single project that has started into clinics, has failed sooner or later. One of the most famous cases is Encenicline, an α7-nicotinic receptor agonist. After having demonstrated efficacy for Cognitive Impairment Associated to Schizophrenia (CIAS) treatment in phase II studies (1), the development was discontinued when phase III studies were unsuccessful on the demonstration of procognitive effect. Several reasons are beyond this failure, but one important aspect is the target. Many pharmaceutical companies have an intense research to find an α7-nicotinic receptor agonist for CIAS treatment, as if this target should be the one. Other companies are investigating on glycine transporter or phosphodiesterase (PDE) modulators. However, little innovation has been added to this scenario. Is maybe this the cause of the drought in CIAS drug discovery?
At Iproteos we are disruptive, unusual and original. As the restless little duck that goes off from the herd, we explore uncharted horizons to identify novel and fruitful paths. Going up and down the hill we found an exquisite enzyme, called prolyl oligopeptidase (POP), which had a beautiful though entangled relationship with mental diseases. Six POP inhibitors have reached preclinical or clinical phases for the treatment of cognition disorders, such as Alzheimer’s or Parkinson Disease, but none for CIAS (2). We jumped in the deep, but with swimming cap and diving flippers, and bet for a research program on POP inhibitors for CIAS treatment.
Figure 1. Prolyl Oligopeptidase (POP) structure. The protease depicts two domains: α/β -hydrolase domain an a β-propeller domain.
And here we are: “The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia”. This is the title of our recent peer-reviewed article published in the European Neuropsychopharmacology journal (3). In this work we demonstrate that IPR19 administration reverses the cognitive deficits of three mouse models (phencyclidine – PCP; MK801 and poly I:C – PIC) which are currently the gold standard ones in the field and that show cognitive impairment and schizophrenia like behavior.
In the following figure (Fig. 2), the results of the Novel Object Recognition (NOR) test are depicted. In NOR, mice are allowed during days to play with two identical objects. The day of the test, one of the objects is replaced for a new one. Once they are sure that the second object is harmful, mice want to explore the new object to satisfy their curiosity. However, if their memory is impaired, they will not remember which one has been already analyzed and thus, animals make no difference between them. Figure 2 shows three bar graphics, each one for the three models. In black bars, it is shown the results from naïve control animals; in grey, it can be appreciated how the respective animal models suffer from memory impairment; and finally, in white, it is observed that IPR19 administration returns the percentage of discrimination index up to control animal levels. Discrimination index is defined as the time that each animal spends with the novel object in comparison with the time that is devoted to the old one.
Figure 2. NOR results of IPR19 treatment.
Analogous to figure 2, in figure 4 the results from the T-maze are outlined. In this test, mice are placed in a T-shaped labyrinth where a food reward is placed at the end of the two arms (see figure 3). At the beginning of the experiment, one of the arms is closed by a sliding door, forcing the mouse to go to the open one. Afterwards, the mouse is returned to the starting point of the maze, but this time both arms are open. If the animal remembers last choice, it will go to the new one, as the mouse will recall taking the reward and leaving empty one arm. On the contrary, if the memory is impaired, the animal will go indistinctly to one arm or the other.
Figure 3. T-maze scheme.
As observed in figure 4, IPR19 treatment is able to reverse the cognition deficit of the animal models to basal conditions (black bars).
Figure 4. T-maze results of IPR19 treatment.
In this work we demonstrated that IPR19 reaches the brain and effectively inhibits POP, ameliorating the cognitive functions of three mouse models with memory impairment. It is a breakthrough in CIAS drug discovery and sheds some light in this difficult field.
It is the time of POP. I’m not talking about music, if you have started reading here. POP is a hot topic nowadays, and not only in CIAS. Recently, Dr. Myöhänen, from the University of Helsinki, demonstrated that the inhibition of POP is able to restore spontaneous motor behavior in α-synuclein mouse models (4). A reduction on α-synuclein aggregation and an increment on clearance have been observed when animals were treated with a POP inhibitor.
It is the time of changing paradigms and opening new avenues. And POP may be the answer to unlock secrets from the brain. Time will tell.
- Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia (2015); Neuropsychopharmacology, 40, 3053-3060
- Peptide POP inhibitors for the treatment of the cognitive symptoms of schizophrenia (2013); Future Medicinal Chemistry, 5 (13), 1-15
- The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia (2016); European Neuropsychopharmacology, pii: S0924-977X(16)32008-9
- Inhibition of Prolyl Oligopeptidase Restores Spontaneous Motor Behavior in the α-Synuclein Virus Vector–Based Parkinson's Disease Mouse Model by Decreasing α-Synuclein Oligomeric Species in Mouse Brain (2016); The Journal of Neuroscience, 36(49):12485-12497