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Oxidative Stress*

Creatine may enhance neuroprotection through energy pathways

by Dr. Michael Lee – Health Editor July 27, 2025

written by Dr. Michael Lee – Health Editor

Creatine Powers More Than Muscle: Brain Boost Unveiled

New Research Illuminates Link Between Supplement and Cognitive Resilience

Creatine, long celebrated for its muscle-building prowess, is now understood to offer significant benefits to the brain, enhancing mood, cognitive function, and resilience through exercise-induced biological pathways.

The Muscle-Brain Connection

A groundbreaking review published in Frontiers in Nutrition explores how creatine impacts both muscle and brain health via the intricate muscle-brain axis. This axis involves myokines, signaling proteins released by muscle cells, which can influence brain function.

These myokines, crossing the blood-brain barrier, are believed to promote neuron growth, foster new neural connections, and improve the efficiency of existing brain circuits. This neurogenesis and neuroplasticity can sharpen cognitive performance and help protect brain cells from inflammation and oxidative stress.

The muscle-brain axis is a dynamic two-way street of communication. Key players include brain-derived neurotrophic factor (BDNF), crucial for memory and neural plasticity, alongside others like cathepsin B, IL-6, IGF-1, irisin, and lactate. BDNF levels naturally rise with exercise, supporting brain health.

Creatine, a molecule vital for energy metabolism in both muscle and brain, is showing promise beyond physical performance.

Creatine: The Energy Regulator

Creatine, a molecule derived from amino acids, is essential for rapid energy availability in the body. It plays a key role in regenerating adenosine triphosphate (ATP), the cell’s primary energy currency. This rapid energy supply is critical for high-demand tissues like muscles and the brain.

Inside cells, creatine is largely converted to phosphocreatine (PCr), which acts as an immediate phosphate reservoir for adenosine diphosphate (ADP), efficiently reforming ATP. This process is particularly vital during intense physical activity, supporting bursts of energy.

Boosting Brain Function Through Exercise

When combined with resistance training, creatine supplementation not only aids muscle growth and strength but may also trigger the release of myokines. These signaling molecules are thought to indirectly benefit the brain, potentially enhancing mood and cognitive functions.

Creatine helps regulate the body’s inflammatory and anti-inflammatory responses, which can be crucial for preventing exercise-induced injuries and maintaining stable body temperatures. Its influence extends to pathways that regulate myokines, such as the mTOR pathway.

For example, creatine supplementation has been linked to increased insulin-like growth factor-1 (IGF-1), a factor known to improve neuronal growth and synaptic plasticity. Creatine’s role in anaerobic performance may also benefit endurance athletes who require sudden power outputs.

Interestingly, lactate, a byproduct of anaerobic metabolism and a myokine, is produced during intense exercise. While creatine doesn’t directly increase lactate, its ATP-boosting effects could indirectly lead to higher BDNF levels by stimulating myokine production.

Potential Therapeutic Applications

Emerging research suggests creatine could offer neuroprotective benefits, potentially aiding in conditions like Huntington’s and Parkinson’s diseases. It may also help protect the central nervous system from concussion-related damage.

Preliminary studies hint at creatine’s positive impact on maternal health during pregnancy and a possible role in reducing the risk of depression. Its ability to combat age-related muscle weakness is another area of active investigation.

Creatine has also shown promise in mental health, influencing the exercise-dependent secretion of neurotransmitters such as serotonin and dopamine, which are vital for neural function and mood regulation. Some evidence suggests a rapid antidepressant effect, potentially enhanced when paired with cognitive behavioral therapy.

A recent pilot trial indicated that combining creatine with CBT yielded greater improvements in depression scores compared to CBT alone. However, larger-scale studies are still required to confirm these findings.

Metabolic Regulation and Beyond

Beyond its effects on energy and mood, creatine supplementation can improve glucose metabolism by enhancing insulin sensitivity. Insulin plays a role in myokine release by facilitating glucose uptake into muscle cells, potentially increasing myokine signaling in response to exercise.

Future Outlook

The link between creatine supplementation, exercise, and increased myokine production highlights a multifaceted impact on both physical performance and brain health. While current research is promising, particularly regarding its anti-inflammatory and mood-boosting potential, further clinical studies are essential.

Researchers are exploring how creatine might directly influence BDNF and other myokine levels, examining pathways like increased phosphocreatine availability and the upregulation of PGC-1α in muscle tissue during exercise. Understanding these intricate connections could solidify creatine’s role in supporting overall physical and mental well-being.

July 27, 2025 0 comments

Health

Blocking GAPDH aggregation protects brain cells and opens new path for stroke therapy

by Dr. Michael Lee – Health Editor July 21, 2025

written by Dr. Michael Lee – Health Editor

New Stroke Therapy Targets Protein Aggregation

Inhibiting GAPDH Could Significantly Reduce Brain Damage

A groundbreaking study suggests that blocking a specific protein’s clumping could revolutionize acute ischemic stroke treatment, offering a new avenue to mitigate devastating brain injuries.

Unlocking a Novel Therapeutic Target

Researchers have identified the protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a key player in stroke-induced brain damage. When the brain suffers from a lack of blood flow followed by its restoration—a process known as ischemia-reperfusion injury—it experiences significant oxidative and nitrosative stress. This stress can lead to neuronal death.

The study, published in the journal iScience, details how GAPDH, a protein with multiple cellular roles, behaves differently under varying stress levels. Low to moderate stress prompts its movement to the cell nucleus, contributing to apoptosis, while severe stress causes it to aggregate, leading to necrosis. This aggregation phase is now seen as a critical target for intervention.

Blocking GAPDH aggregation offers a promising new path for stroke therapy by protecting brain cells.

Study Reveals Promising Results in Animal Models

To investigate this, scientists utilized a mouse model of stroke by temporarily blocking the middle cerebral artery. They observed that GAPDH aggregates began to form in the brain’s striatum approximately 12 hours after reperfusion, even before infarction became evident. This temporal relationship strongly suggests a causal link between GAPDH aggregation and subsequent brain damage.

Further experiments involved genetically modified mice engineered to express a variant of GAPDH that inhibits aggregation. These mice exhibited significantly reduced infarct volumes in both the cortex and striatum compared to their control counterparts. Their neurological function also showed marked improvement, indicating that preventing GAPDH aggregation effectively lessened the brain damage.

Pharmacological Intervention Shows Therapeutic Potential

Beyond genetic manipulation, the researchers explored pharmacological inhibition. They identified a tripeptide, GAI-17, as a potent inhibitor of GAPDH aggregation. In the MCAO mouse model, administering GAI-17 one hour before, immediately after, and twelve hours after reperfusion significantly reduced infarct volumes, particularly in the cortical penumbra—the area surrounding the core ischemic region.

Crucially, the study established a therapeutic window for GAI-17. Treatments administered up to six hours post-reperfusion demonstrated significant protective effects, improving neurological deficits. However, interventions at nine hours post-reperfusion showed no protective benefits, defining a critical window for intervention.

According to the World Health Organization, stroke is the second leading cause of death globally, responsible for approximately 6 million deaths annually (WHO). Current treatments like recombinant tissue plasminogen activator have a narrow therapeutic window of 4.5 hours, highlighting the urgent need for alternative therapies with extended efficacy.

Study Limitations and Future Directions

While promising, the research acknowledges certain limitations. The study focused exclusively on transient ischemia with reperfusion, not permanent strokes. The assessments were also short-term, up to 48 hours post-event, and did not explore long-term effects. Furthermore, potential off-target effects of GAI-17 were not fully investigated, and sex-based differences in susceptibility were not extensively studied.

Despite these limitations, the findings strongly suggest that inhibiting GAPDH aggregation represents a viable therapeutic strategy for acute ischemic stroke. This approach could offer a much-needed extension of the treatment window, potentially saving countless lives and reducing the debilitating effects of stroke.

July 21, 2025 0 comments

Health

c-Fos exhibits a dual role in memory formation and Alzheimer’s disease

by Dr. Michael Lee – Health Editor June 14, 2025

written by Dr. Michael Lee – Health Editor

c-Fos Gene: A Double-Edged Sword in Brain Health and Alzheimer’s

c-Fos: A Critical Gene in Memory and Brain Function, with Implications for Alzheimer’s Disease

The immediate-early gene c-Fos plays a crucial role in how our brains respond to stimuli, but its dysregulation may contribute to Alzheimer’s disease. Initially identified as a proto-oncogene, c-Fos is essential for neural activity, synaptic plasticity, and stress responses. Its dual nature complicates the understanding of neurodegenerative diseases.

The Role of c-Fos in Healthy Brains

c-Fos expression is seen in the hippocampus, amygdala, and cortex. These areas are integral to our ability to learn and remember. This gene expression is not limited to neurons. Glial cells, including astrocytes and microglia, also exhibit c-Fos induction under stress or inflammation. c-Fos helps with memory consolidation and synaptic plasticity.

During new experiences, c-Fos peaks; as we become habituated, it diminishes. This highlights its adaptive role in neural responses. Disruptions in c-Fos hinder long-term memory. The sensitivity of c-Fos to stimulus intensity and frequency is key to encoding and recalling memories.

c-Fos’s Double-Edged Sword in Alzheimer’s

In Alzheimer’s patients, c-Fos expression is elevated. This increase correlates with amyloid-β (Aβ) accumulation and cognitive decline. Aβ stabilizes c-Fos via O-GlcNAcylation, thus promoting apoptosis. Chronic c-Fos activation disrupts synaptic function, furthering neuroinflammation, creating a destructive cycle.

Studies in Alzheimer’s models reveal hippocampal hyperactivity and neuronal loss. This suggests a role in early disease markers. Pathological effects stem from dysregulated calcium signaling, oxidative stress, and epigenetic modifications. Constitutive CREB activation and mitochondrial dysfunction worsen neuronal damage.

The Mechanisms and Consequences of c-Fos Dysregulation

c-Fos encourages apoptosis via ATF3 and pro-apoptotic genes such as Bim and cytochrome c. This pathway is hyperactivated in Alzheimer’s, causing widespread neuronal death. The ERK/FOS axis also intensifies inflammatory responses, illustrating c-Fos as a mediator of both apoptosis and neuroinflammation.

Oxidative stress in Alzheimer’s activates MAPK pathways, thus upregulating c-Fos and disrupting mitochondrial function. This exacerbates ROS production and inflammatory cytokine release, further damaging neurons. The interplay between oxidative stress and c-Fos underscores its central role in disease progression.

According to the Alzheimer’s Association, the disease affects an estimated 6.7 million Americans age 65 and older in 2023 (Alzheimer’s Association).

Toward Therapeutic Interventions

c-Fos has a dual role, supporting memory in healthy brains while driving neurodegeneration in Alzheimer’s. Its dysregulation in Alzheimer’s involves multiple pathways. Targeting c-Fos modulation may offer potential therapeutic avenues to mitigate cognitive decline.

Future research should focus on c-Fos-specific interventions. These interventions aim to disrupt its pathological effects while preserving its physiological functions. This could potentially improve the treatment and management of Alzheimer’s disease and other related neurological conditions.

June 14, 2025 0 comments

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