Some compounds belonging to the different individual groups will be briefly described.
Type M1 muscarinic receptor agonist drugs
As described in the previous article, currently the drugs used for Alzheimer's disease include inhibitors of? Acetylcholinesterase. The disadvantage of the use of these drugs is due to the fact that to function they are based on the integrity of the nervous structures, which in the Alzheimer's patient continue to degenerate, making, over time, the inhibitors of the? ™ less and less effective acetylcholinesterases. Furthermore, another disadvantage that these drugs present is the lack of selectivity towards specific receptors. Currently numerous scientific studies have shown that the stimulation of muscarinic receptors of type M1, but not M2, is able to lead to a reduction in β-amyloid levels. A reduction in β-amyloid levels means slowing the progression of Alzheimer's disease, which, as previously described, is also characterized by β-amyloid accumulation.
As for the muscarinic M1 receptors, they are abundantly localized in the hippocampus and in the cortex, two brain areas where the greatest cholinergic deficit occurs, due to the progressive loss of cholinergic neurons. It is also known that M1 receptors are involved in short-term memory.
Among the various compounds currently being tested, which act on the muscarinic M1 receptor, interestingly appear to be AF102B and Talsaciclidina . In fact, long-term treatment with these drugs has led to a reduction in β-amyloid levels in the cerebrospinal fluid of patients with Alzheimer's disease. This has led to the hypothesis that the increase in cholinergic function may slow down the progression of the disease by reducing the accumulation of β-amyloid.
Another interesting but limited drug is Xanomelin, which acts as an M1 / M4 agonist. This drug leads to improvements in cognitive functions and a reduction in behavioral disorders that sometimes accompany patients with Alzheimer's disease. Unfortunately Xanomelina has adverse effects on the gastrointestinal level and for this reason its use is limited. Currently, however, it is being studied for the treatment of psychiatric disorders such as schizophrenia.
Nicotinic receptor agonist drugs
The loss of cholinergic neurons in Alzheimer's patients has suggested that nicotinic receptors could be a useful therapeutic target. Recently, research has focused on α7-type nicotinic receptor agonists, since it is predominant in brain regions that show cholinergic degeneration during Alzheimer's disease. Furthermore, it was observed that stimulation of α7-type nicotinic receptors protects cells from β-amyloid-induced degeneration. Among the different compounds synthesized, ABT-107 has aroused particular interest, showing cognitive improvements in monkeys, rats and mice. It has also been observed that this compound induces an improvement in short-term memory when given in combination with donepezil, an inhibitor of? Acetylcholinesterase. ABT-107 was also recently tested in humans in healthy controls, and was shown to be well tolerated, with good pharmacokinetics and only mild adverse effects.Another compound, still in the experimental phase, which seems to give promising answers is EVP-6124 . In the clinical phase, it was initially tested on 48 participants who presented with mild to moderate Alzheimer's disease. These patients were treated for 30 days with EVP-6124, in combination with a classic? Acetylcholinesterase inhibitor. The results obtained indicated that the side effects were not serious and also some improvements were observed in the level of attention, verbal fluidity and executive functions (for executive functions s'? ™ means a set of necessary processes to perform a specific task, such as working memory, problem solving, design and more).
Anti β-amyloid antibodies
Anti β-amyloid monoclonal antibodies are used, through passive immunization, in an attempt to reduce β-amyloid protein levels. Among these monoclonal antibodies, still in the experimental phase, bapineuzumab can be found, for example. Phase 2 (or therapeutic-exploratory) studies have been conducted, where the therapeutic activity of the potential drug begins to be investigated, that is its ability to produce the desired healing effects on the human organism. It was observed that in one trial bapineuzumab led to the reduction of β-amyloid protein. Unfortunately, in other clinical trials no differences in cognitive abilities were observed between the group treated with the potential drug and the placebo group. Regarding the side effects observed in both trials, 10% of the individuals who took part in the trial showed vasogenic cerebral edema, probably associated with the highest dose of the drug. Furthermore, following treatment with bapineuzumab, a significant reduction in tau protein levels was observed in patients with Alzheimer's disease.
Another monoclonal antibody that uses β-amyloid as a target is solanezumab . Unlike bapineuzumab, which targets amyloid plaques, solanezumab is able to recognize some variants of β-amyloid protein (β-amyloid 13-28) that are not recognized by solanezumab. Furthermore, another very important difference is the ability of solanezumab to bind to soluble β-amyloid, which has recently been shown to be harmful even before forming plaques. Recent studies show that solanezumab reduces the accumulation of β-amyloid at the level of neuritic plaques. With regard to the adverse effects that appear to be due to the administration of solanezumab, to date, slight chills, nausea, vomiting, headache, back pain and cough have been manifested during the experimental phase.
Γ-secretase inhibitors
.First of all, let's briefly summarize what senile plaques are made of. The main protein component of senile plaques is formed by β-amyloid (as described in the previous chapters). β-amyloid (Aβ) derives from the enzymatic degradation of APP (Amyloid Precursor Protein), a transmembrane protein expressed ubiquitously in nerve cells. The metabolic degradation of APP can follow two ways: a pathway defined as amyloidogenic by the β-secretase which splits APP into two fragments of which one soluble N-terminal and one C-terminal transmembrane which is subsequently degraded by γ-secretase with subsequent formation of β-amyloid. APP degradation can also follow a pathway called non-amyloidogenic, which will be discussed later.
Among the γ-secretase inhibitors currently in clinical trials, there are begacestat, a drug able to selectively inhibit the cleavage of the Aβ precoritator protein (APP), consequently leading to a reduction in Aβ formation. In studies conducted on transgenic animal models overexpressing APP, oral treatment with begacestat induced a reduction in the brain, plasma and cerebrospinal fluid of Aβ levels. Not only that, on a cognitive level, a dose-dependent inversion of the contextual memory deficits (ie the ability to remember the source and circumstances of a specific event) was also observed.
