Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases.

Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.

Headache Is Associated with Low Systolic Blood Pressure and Psychosocial Problems in German Adolescents: Results from the Population-Based German KiGGS Study.

Studies have reported controversial results on the relationship between headache and blood pressure. The aim of this post hoc study was twofold: first, to further investigate this relationship and, second, to assess the impact of psychosocial factors on this association in a population-based study of German children and adolescents. The analysis was conducted on study participants aged between 11 and 17 years (n = 5221, weighted from the total study cohort) from the nationwide German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Health-related quality of life was assessed by self- and parent-rated German-language KINDL-R questionnaires (Children's Quality of Life Questionnaire), while mental problems were analyzed using the Strengths and Difficulties Questionnaire (SDQ). Our findings confirmed that blood pressure was significantly lower in adolescents reporting episodes of headache than in those without headache (114.0 ± 10.2 mmHg vs. 115.5 ± 11.0 mmHg, p < 0.001). Logistic regression models adjusted to sex, age, body mass index, contraceptive use, and serum magnesium concentration demonstrated that headache was significantly associated with self-rated KINDL-R (Exp(B) = 0.96, 95% confidence interval (95% Cl) = 0.96-0.97, p < 0.001), parent-rated KINDL-R (Exp(B) = 0.97, 95% CI = 0.96-0.98, p < 0.001), as well as self-rated SDQ (Exp(B) = 1.08, 95% CI = 1.07-1.10, p < 0.001), and parent-rated SDQ (Exp(B) = 1.05, 95% CI = 1.04-1.06, p < 0.001). There was evidence that quality of life and mental problems mediated the effect of blood pressure on headache, as revealed by mediation models. Our results from the nationwide, representative KiGGS survey showed that low blood pressure is a significant predictor of headache, independent of quality of life and mental problems. However, these psychosocial factors may mediate the effect of blood pressure on headache in a still unknown manner.