Neuroinflammation, i.e. self-propelling progressive cycle of microglial activation and neuron damage, as well as improper protein folding, are recognized as major culprits of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in several proteins have been linked to ALS pathogenesis, including the G93A mutation in the superoxide dismutase 1 (SOD1) enzyme. SOD1(G93A) mutant is prone to aggregate thus inducing both oxidative stress and neuroinflammation. In this study we used hSOD1(G93A) microglial cells to investigate the effects of the antioxidant and anti-inflammatory cyclic dipeptide (His-Pro) on LPS-induced inflammasome activation. We found that cyclo(His-Pro) inhibits NLRP3 inflammasome activation by reducing protein nitration via reduction in NO and ROS levels, indicative of lower peroxynitrite generation by LPS. Low levels in peroxynitrite are related to NF-κB inhibition responsible for iNOS down-regulation and NO dampening. On the other hand, cyclo(His-Pro)-mediated ROS attenuation, not linked to Nrf2 activation in this cellular model, is ascribed to increased soluble SOD1 activity due to the up-regulation of Hsp70 and Hsp27 expression. Conclusively, our results, besides corroborating the anti-inflammatory properties of cyclo(His-Pro), highlight a novel role of the cyclic dipeptide as a proteostasis regulator, and therefore a good candidate for the treatment of ALS and other misfolding diseases.

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by degeneration of upper motor neurons in the brainstem and lower motor neurons in the spinal cord. Multiple mechanisms of motor neuron injury have been implicated, including more than 20 different genetic factors. The pathogenesis of ALS consists of two stages: an early neuroprotective stage and a later neurotoxic. During early phases of disease progression, the immune system through glial and T cell activities provides anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a rapidly succeeding neurotoxic phase develops. A well-orchestrated purine-mediated dialog among motor neurons, surrounding glia and immune cells control the beneficial and detrimental activities occurring in the nervous system. In general, low adenosine triphosphate (ATP) concentrations protect cells against excitotoxic stimuli through purinergic P2X4 receptor, whereas high concentrations of ATP trigger toxic P2X7 receptor activation. Finally, adenosine is also involved in ALS progression since A2A receptor antagonists prevent motor neuron death. Given the complex cellular cross-talk occurring in ALS and the recognized function of extracellular nucleotides and adenosine in neuroglia communication, the comprehensive understanding of purinome dynamics might provide new research perspectives to decipher ALS and help to design more efficient and targeted drugs. This review will focus on the purinergic players involved in ALS etiology and disease progression and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity.

Brain-computer interfaces (BCIs) enable communication with others and allow machines or computers to be controlled in the absence of motor activity. Clinical studies evaluating neural prostheses in amyotrophic lateral sclerosis (ALS) patients have been performed; however, to date, no study has reported that ALS patients who progressed from locked-in syndrome (LIS), which has very limited voluntary movement, to a completely locked-in state (CLIS), characterized by complete loss of voluntary movements, were able to continue controlling neural prostheses. To clarify this, we used a BCI system to evaluate three late-stage ALS patients over 27 months. We employed steady-state visual evoked brain potentials elicited by flickering green and blue light-emitting diodes to control the BCI system. All participants reliably controlled the system throughout the entire period (median accuracy: 83.3%). One patient who progressed to CLIS was able to continue operating the system with high accuracy. Furthermore, this patient successfully used the system to respond to yes/no questions. Thus, this CLIS patient was able to operate a neuroprosthetic device, suggesting that the BCI system confers advantages for patients with severe paralysis, including those exhibiting complete loss of muscle movement.

Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, are characterized by the progressive loss of neurons in specific regions of the brain and/or spinal cord. Neuronal cell loss typically occurs by either apoptotic or necrotic mechanisms. Oxidative stress and nitrosative stress, along with excitotoxicity and caspase activation, have all been implicated as major underlying causes of neuronal cell death. Diverse nutraceuticals (bioactive compounds found in common foods) have been shown to have neuroprotective effects in a variety of in vitro and in vivo disease models. In the current study, we compared the neuroprotective effects of two polyphenolic compounds, rosmarinic acid and carnosic acid, which are both found at substantial concentrations in the herb rosemary. The capacity of these compounds to rescue primary cultures of rat cerebellar granule neurons (CGNs) from a variety of stressors was investigated. Both polyphenols significantly reduced CGN death induced by the nitric oxide donor, sodium nitroprusside (nitrosative stress). Rosmarinic acid uniquely protected CGNs from glutamate-induced excitotoxicity, while only carnosic acid rescued CGNs from caspase-dependent apoptosis induced by removal of depolarizing extracellular potassium (5K apoptotic condition). Finally, we found that carnosic acid protects CGNs from 5K-induced apoptosis by activating a phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The shared and unique neuroprotective effects of these two compounds against diverse modes of neuronal cell death suggest that future preclinical studies should explore the potential complementary effects of these rosemary polyphenols on neurodegenerative disease progression.