Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Individual and Combined Effect of MAO-A/MAO-B Gene Variants and Adverse Childhood Experiences on the Severity of Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a mood disorder with a high prevalence worldwide that causes disability and, in some cases, suicide. Although environmental factors play a crucial role in this disease, other biological factors may predispose individuals to MDD. Genetic and environmental factors influence mental disorders; therefore, a potential combined effect of MAO-A/MAO-B gene variants may be a target for the study of susceptibility to MDD. This study aimed to evaluate the effects of MAO-A and -B gene variants when combined with adverse childhood experiences (ACEs) on the susceptibility and severity of symptoms in MDD. METHODS: A case-control study was performed, including 345 individuals, 175 MDD cases and 170 controls. Genotyping was performed using real-time PCR with hydrolysis probes. The analysis of the rs1465107 and rs1799836 gene variants of MAO-A and -B, respectively, was performed either alone or in combination with ACEs on the severity of depression, as determined through specific questionnaires, including DSM-IV diagnostic criteria for MDD. RESULTS: According to individual effects, the presence of ACEs, as well as the allele G of the rs1465107 of MAO-A, is associated with a higher severity of depression, more significantly in females. Furthermore, the allele rs1799836 G of MAO-B was associated with the severity of depression, even after being adjusted by gene variants and ACEs (IRR = 1.67, p = 0.01). In males, the allele rs1799836 G of MAO-B was shown to interact with SNP with ACEs (IRR = 1.70, p < 0.001). According to combined effect analyses, the severity of depression was associated with ACEs when combined with either allele rs1465107 of MAO-A or allele rs17993836 of MAO-B, whereas SNP risk association was influenced by gender. CONCLUSIONS: The severity of depression is related to either individual or combined effects of temperamental traits and genetic susceptibility of specific genes such as MAO-A and MAO-B.

Analysis of the rs13306560 functional variant in the promoter region of the MTHFR gene in sporadic Parkinson´s disease.

OBJECTIVE: Among susceptibility genes for Sporadic Parkinson´s Disease (SPD), the MTHFR gene has been suggested as candidate. The A allele of the functional variant rs13306560 in its promoter region has been liked to decreased transactivation capacity. Therefore, we sought to determine a possible association of the rs13306560 and SPD. METHODS: In total, 237 individuals were genotyped, 113 patients with SPD diagnosed according to the Queen Square Brain Bank criteria and 124 neurologically healthy controls. Genotyping was performed using TaqMan probes for the rs13306560 and real-time PCR. RESULTS: The A allelle was associated to protection in SPD, under the dominant model, (OR=0.22, C.I.=[0.048-1.080], p=0.04), nevertheless, after logistic regression analysis with adjustment for gender, resulted only in a trend (Exp (ß)=0.211, [I.C. 95.0%, 0.042-1.057], p=0.058). CONCLUSION: Although further studies are needed, our data suggest an important role of the MTHFR gene variants in the fine-tuning regulation of one-carbon metabolism in the brain.