Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca(2+) overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1(G93A) ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS.

Angiogenin protects motoneurons against hypoxic injury.

Cells can adapt to hypoxia through the activation of hypoxia-inducible factor-1 (HIF-1), which in turn regulates the expression of hypoxia-responsive genes. Defects in hypoxic signaling have been suggested to underlie the degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). We have recently identified mutations in the hypoxia-responsive gene, angiogenin (ANG), in ALS patients, and have shown that ANG is constitutively expressed in motoneurons. Here, we show that HIF-1alpha is sufficient and required to activate ANG in cultured motoneurons exposed to hypoxia, although ANG expression does not change in a transgenic ALS mouse model or in sporadic ALS patients. Administration of recombinant ANG or expression of wild-type ANG protected motoneurons against hypoxic injury, whereas gene silencing of ang1 significantly increased hypoxia-induced cell death. The previously reported ALS-associated ANG mutations (Q12L, K17I, R31K, C39W, K40I, I46V) all showed a reduced neuroprotective activity against hypoxic injury. Our data show that ANG plays an important role in endogenous protective pathways of motoneurons exposed to hypoxia, and suggest that loss of function rather than loss of expression of ANG is associated with ALS.

Monostable array-enhanced stochastic resonance.

We present a simple nonlinear system that exhibits multiple distinct stochastic resonances. By adjusting the noise and coupling of an array of underdamped, monostable oscillators, we modify the array's natural frequencies so that the spectral response of a typical oscillator in an array of N oscillators exhibits N-1 different stochastic resonances. Such families of resonances may elucidate and facilitate a variety of noise-mediated cooperative phenomena, such as noise-enhanced propagation, in a broad class of similar nonlinear systems.

Noninvasive control of stochastic resonance.

External feedback can enhance (or depress) the response of a noisy bistable system to monochromatic signals, significantly magnifying its natural stochastic resonance. We compare and contrast a variety of such feedback strategies, using both numerical simulations and analog electronic experiments. These noninvasive control techniques are especially valuable for noisy bistable systems that are difficult or impossible to modify internally.

Smoking and patterns of bone loss in early-onset periodontitis.

BACKGROUND: The aims of this study were to investigate the extent and distribution of bone loss in subjects with early-onset periodontitis (EOP) referred for periodontal care and to study the relationship between smoking and EOP. METHODS: A total of 71 consecutive referrals (21 male, 50 female) under 35 years old, who were otherwise healthy, with a clinical diagnosis of severe periodontitis were recruited for the study. Bone loss was measured from available radiographs using a Schei ruler to identify 2 patterns of destruction: localized (LEOP) in 41 (58%) and generalized early-onset periodontitis (GEOP) in 30 (42%) subjects. RESULTS: The study population had a mean of 25.0 (SD 2.4) teeth, excluding third molars, and mean bone loss of 28.7% (SD 13.0). Bone loss was more severe in the maxilla, 30.9% (SD 13.8) compared with 26.6% (SD 14.0) in the lower arch. More than one-third (36%) of the teeth examined had at least 30% bone loss. Mean smoking experience was 9.2 pack years (SD 5.6), and 39 (55%) of the EOP subjects smoked. Smokers had significantly more maxillary bone loss than non-smokers. A much higher proportion of GEOP (70%) currently smoked compared with 44% of LEOP, P = 0.029. CONCLUSIONS: It is concluded that young adults with early-onset forms of periodontitis often have advanced periodontal destruction before they are referred for specialist care. In addition, there was a relationship between smoking and severe bone destruction in subjects with EOP, particularly those with generalized disease.