Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death in the central nervous system. Vitamin D supplementation increases antioxidant activity, reduces inflammation and improves motor neuron survival. We have previously demonstrated that vitamin D3 supplementation at 10× the adequate intake improves functional outcomes in a mouse model of ALS.ObjectiveTo determine whether vitamin D deficiency influences functional and disease outcomes in a mouse model of ALS.MethodsAt age 25 d, 102 G93A mice (56 M, 46 F) were divided into two vitamin D3 groups: 1) adequate (AI; 1 IU D3/g feed) and 2) deficient (DEF; 0.025 IU D3/g feed). At age 113 d, tibialis anterior (TA), quadriceps (quads) and brain were harvested from 42 mice (22 M and 20 F), whereas the remaining 60 mice (34 M and 26 F) were followed to endpoint.ResultsDuring disease progression, DEF mice had 25% (P = 0.022) lower paw grip endurance AUC and 19% (P = 0.017) lower motor performance AUC vs. AI mice. Prior to disease onset (CS 2), DEF mice had 36% (P = 0.016) lower clinical score (CS) vs. AI mice. DEF mice reached CS 2 six days later vs. AI mice (P = 0.004), confirmed by a logrank test which revealed that DEF mice reached CS 2 at a 43% slower rate vs. AI mice (HR = 0.57; 95% CI: 0.38, 1.74; P = 0.002). Body weight-adjusted TA (AI: r = 0.662, P = 0.001; DEF: r = 0.622, P = 0.006) and quads (AI: r = 0.661, P = 0.001; DEF: r = 0.768; P<0.001) weights were strongly correlated with age at CS 2.ConclusionVitamin D3 deficiency improves early disease severity and delays disease onset, but reduces performance in functional outcomes following disease onset, in the high-copy G93A mouse.

Vitamin D has been demonstrated to influence multiple aspects of amyotrophic lateral sclerosis (ALS) pathology. Both human and rodent central nervous systems express the vitamin D receptor (VDR) and/or its enzymatic machinery needed to fully activate the hormone. Clinical research suggests that vitamin D treatment can improve compromised human muscular ability and increase muscle size, supported by loss of motor function and muscle mass in animals following VDR knockout, as well as increased muscle protein synthesis and ATP production following vitamin D supplementation. Vitamin D has also been shown to reduce the expression of biomarkers associated with oxidative stress and inflammation in patients with multiple sclerosis, rheumatoid arthritis, congestive heart failure, Parkinson's disease and Alzheimer's disease; diseases that share common pathophysiologies with ALS. Furthermore, vitamin D treatment greatly attenuates hypoxic brain damage in vivo and reduces neuronal lethality of glutamate insult in vitro; a hallmark trait of ALS glutamate excitotoxicity. We have recently shown that high-dose vitamin D3 supplementation improved, whereas vitamin D3 restriction worsened, functional capacity in the G93A mouse model of ALS. In sum, evidence demonstrates that vitamin D, unlike the antiglutamatergic agent Riluzole, affects multiple aspects of ALS pathophysiology and could provide a greater cumulative effect.

BackgroundWe previously demonstrated that dietary vitamin D3 at 10x the adequate intake (AI) attenuates the decline in functional capacity in the G93A mouse model of ALS. We hypothesized that higher doses would elicit more robust changes in functional and disease outcomes.ObjectiveTo determine the effects of dietary vitamin D3 at 50xAI on functional outcomes (motor performance, paw grip endurance) and disease severity (clinical score), as well as disease onset, disease progression and lifespan in the transgenic G93A mouse model of ALS.MethodsStarting at age 25 d, 100 G93A mice (55 M, 45 F) were provided ad libitum with either an adequate (AI; 1 IU D3/g feed) or high (HiD; 50 IU D3/g feed) vitamin D3 diet.ResultsHiD females consumed 9% less food corrected for body weight vs. AI females (P = 0.010). HiD mice had a 12% greater paw grip endurance over time between age 60–141 d (P = 0.015), and a 37% greater score during disease progression (P = 0.042) vs. AI mice. Although HiD females had a non-significant 31% greater CS prior to disease onset vs. AI females, they exhibited a significant 20% greater paw grip endurance AUC (P = 0.020) when corrected for clinical score.ConclusionDietary D3 supplementation at 50x the adequate intake attenuated the decline in paw grip endurance, but did not influence age at disease onset, hindlimb paralysis or endpoint in the transgenic G93A mouse model of ALS. Furthermore, females may have reached the threshold for vitamin D3 toxicity as evidence by reduced food intake and greater disease severity prior to disease onset.

Although disease outcomes were not affected, D(3) supplementation at 10-fold the AI improved paw grip endurance and motor performance in the transgenic G93A mouse model of ALS, specifically in males.

Background Cessation of blood flow during out-of-hospital cardiac arrest (OHCA) results in microvascular thrombosis, protracted hypoperfusion after return of spontaneous circulation and damage to vital organs. We tested the hypothesis that pre-arrest antiplatelet and anticoagulant medication use would be associated with less post-arrest organ dysfunction and better outcomes. Methods We included OHCA patients treated from January 2005 to October 2014 at a single academic medical center. We combined our prospective OHCA registry of clinical and demographic data with a structured chart review to abstract home antiplatelet and anticoagulant medications. We fit unadjusted and adjusted regression models to test the association of antiplatelet and anticoagulant medication use with early post-arrest illness severity, survival and functionally favorable recovery. Results Of 1054 subjects, 295 (28%) were prescribed an antiplatelet agent and 147 (14%) were prescribed an anticoagulant prior to arrest. In adjusted models, antiplatelet agents were associated with lower post-arrest illness severity (adjusted OR 0.50 95% CI 0.33-0.77), greater odds of survival to discharge (adjusted OR 1.74 95% CI 1.08-2.80) and greater odds favorable functional outcome (adjusted OR 2.11 95% CI 1.17-3.79). By contrast, anticoagulation via any agent was not associated with illness severity, survival to discharge or favorable outcome. Conclusion Preventing intra-arrest and post-arrest microvascular thrombosis via antiplatelet agents could represent a novel therapeutic target to improve outcomes after OHCA.