ACTH (4-10)

ACTH (4-10) can cross the blood–brain barrier and specifically bind to MC3R and MC4R in the central nervous system, making it a core tool for studying neuroprotection, neural plasticity, and neurotransmitter regulation. Its main applications focus on neuronal function regulation and pathological mechanism exploration of neurodegenerative diseases.

In neuronal function studies, ACTH (4-10) is commonly used in in vitro cell experiments to examine its effects on neuronal survival, proliferation, differentiation, and synaptic plasticity. Studies have shown that this peptide promotes the phosphorylation of the transcription factor CREB by activating the adenylate cyclase (AC)–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling pathway, thereby upregulating the expression of brain‑derived neurotrophic factor (BDNF). As an important neurotrophic factor, BDNF significantly promotes neuronal survival, synaptic growth, and maintenance of plasticity, providing key experimental evidence for its neuroprotective mechanism.

In exploring the pathological mechanisms of neurodegenerative diseases, ACTH (4-10) is widely used in animal models of Alzheimer's disease, Parkinson's disease, and other disorders. In mouse dementia models induced by amyloid‑β (Aβ), intraperitoneal injection of ACTH (4-10) for 4 consecutive weeks significantly reduces Aβ deposition and tau hyperphosphorylation in the mouse brain and upregulates synaptophysin expression. Morris water maze tests confirm that the escape latency of the treated group is shortened by 35%, and the time spent in the target quadrant is doubled, clearly demonstrating its cognitive‑improving effects and related pathological mechanisms.

As an active fragment of ACTH, ACTH (4-10) does not possess the core function of full‑length ACTH in stimulating cortisol secretion, but it can negatively regulate the hypothalamic–pituitary–adrenal (HPA) axis. Therefore, it is widely used in studies on HPA axis regulation and stress responses. The HPA axis is the body's core endocrine axis for stress response; its overactivation leads to abnormally elevated cortisol levels, which damage hippocampal neurons and cause cognitive impairment, mood disorders, and other problems.

In research, ACTH (4-10) is often used to establish stress‑related animal models and explore its regulatory effects and mechanisms on the HPA axis. Experiments confirm that this peptide reduces excessive ACTH secretion from the pituitary by inhibiting hypothalamic corticotropin‑releasing hormone (CRH) release, thereby lowering adrenal cortisol output and preventing chronic hypercortisolism‑induced damage to tissues and organs. This property makes it a valuable tool for studying endocrine disorders and mood disturbances caused by chronic stress. In addition, studies have found that ACTH (4-10) can regulate neurotransmitter balance under stress, promote the release of excitatory neurotransmitters such as dopamine and acetylcholine, attenuate excessive inhibitory effects of γ‑aminobutyric acid (GABA), and improve signal transmission efficiency in neural circuits, offering new insights into the pathological mechanisms of stress‑related psychiatric disorders.

ACTH (4-10) can regulate immune cell function and inflammatory responses by binding to MC1R, MC3R, and MC5R on immune cell surfaces, making it widely used in basic research on immunomodulation and inflammatory mechanisms. Its main mechanisms involve inhibiting pro‑inflammatory factor release and regulating immune cell differentiation.

In inflammatory mechanism research, ACTH (4-10) is frequently used in the establishment and intervention of various inflammation models. For instance, in animal models of spinal cord injury (SCI), treatment with ACTH (4-10) significantly reduces the expression of pro‑inflammatory factors such as IL‑6 and IL‑8 at the injury site. Notably, in severe SCI models, IL‑6 and IL‑8 levels in the 3‑hour treatment group are significantly lower than those in the 6‑hour group, confirming that it alleviates secondary damage after spinal cord injury by suppressing inflammation and providing important evidence for exploring inflammatory mechanisms and intervention strategies for SCI.

In in vitro immune cell experiments, this peptide inhibits excessive activation of macrophages and T cells, reduces the release of pro‑inflammatory factors including tumor necrosis factor‑α (TNF‑α) and IL‑6, promotes the expression of anti‑inflammatory factors such as IL‑10, regulates T‑cell differentiation, and inhibits Th17 cell overactivation, serving as a key tool for studying immune mechanisms in autoimmune diseases.

Neuroprotection represents the most promising drug development direction for ACTH (4-10), targeting acute nerve injuries such as ischemic stroke, traumatic brain injury, and spinal cord injury, as well as neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. It reduces disability and delays disease progression by inhibiting neuronal apoptosis, alleviating inflammation, and promoting damaged nerve repair.

In the development of acute nerve injury drugs, ACTH (4-10) offers the advantage of rapid blood–brain barrier penetration, direct action on injured neurons, and minimal toxicity.

For example, in rat middle cerebral artery occlusion (MCAO) models, intracerebroventricular injection of ACTH (4-10) results in significantly lower neurological deficit scores at 72 hours after reperfusion, approximately 40% reduction in cerebral infarct volume, decreased apoptosis in the hippocampal CA1 region, and markedly increased BDNF expression compared with the control group, confirming its strong protective effect against acute cerebral ischemic injury and providing solid experimental support for subsequent drug development.

For spinal cord injury, ACTH (4-10) promotes functional recovery by suppressing inflammation and reducing neuronal apoptosis; its derivatives have entered preclinical toxicity testing, showing good translational potential.

In neurodegenerative disease drug development, ACTH (4-10) delays disease progression through multi‑target actions. For Alzheimer's disease, it reduces Aβ deposition, inhibits tau hyperphosphorylation, promotes neurotrophic factor expression, and improves cognitive function. For Parkinson's disease, it protects dopaminergic neurons in the substantia nigra and alleviates motor dysfunction. Preclinical studies of related derivatives have achieved phased progress, with some modified peptides showing enhanced neuroprotective effects in animal models.

Based on its regulatory effects on the central nervous system, ACTH (4-10) holds great value in cognition‑enhancing drug development, targeting Alzheimer's disease, vascular dementia, mild cognitive impairment, and other conditions. It improves learning, memory, and cognitive function by enhancing synaptic transmission efficiency, promoting neurotrophic factor expression, and balancing neurotransmitters.

Preclinical studies indicate that ACTH (4-10) enhances long‑term potentiation (LTP) in the hippocampus and promotes synaptic plasticity. Since the hippocampus is the core brain region for learning and memory, enhanced synaptic plasticity significantly improves cognitive function.

Additionally, this peptide regulates central neurotransmitter balance, promotes the release of excitatory neurotransmitters such as dopamine and acetylcholine, improves neural circuit signaling, and alleviates cognitive decline. In human trials, subjects receiving ACTH (4-10) showed significantly greater improvements in reaction time during continuous performance tasks compared with the placebo group, confirming its ability to relieve mental fatigue and improve attention and response speed, providing clinical evidence for cognition‑enhancing drug development. Currently, researchers are chemically modifying ACTH (4-10) to further improve stability and blood–brain barrier permeability; the cognition‑enhancing effects of related derivatives have been validated in animal dementia models, showing promising clinical translation prospects.

Based on its anti‑inflammatory and immunomodulatory activities, ACTH (4-10) has broad prospects in drug development for autoimmune and inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and secondary inflammation after spinal cord injury. It alleviates symptoms and slows disease progression by suppressing inflammation and restoring immune balance.

In autoimmune disease drug development, ACTH (4-10) reduces autoimmune‑mediated tissue damage by regulating T‑cell differentiation and inhibiting pro‑inflammatory factor release.

For multiple sclerosis, it inhibits immune cell attack on myelin sheaths, reduces neuroinflammation, and preserves neural function; preclinical studies confirm its efficacy in alleviating symptoms in model animals, laying a foundation for future clinical trials. In inflammatory bowel disease, it suppresses intestinal mucosal inflammation, reduces pro‑inflammatory factor release, and promotes mucosal repair, and is currently undergoing animal validation. For secondary inflammation after spinal cord injury, ACTH (4-10) reduces neuron damage by lowering IL‑6, IL‑8, and other pro‑inflammatory factors, providing a new drug development direction for SCI treatment.