Semax

1. Introduction

The contemporary landscape of neuropharmacology is undergoing a paradigm shift, moving away from small-molecule agents that bluntly force neurotransmitter release or blockade receptors, and towards the nuanced field of “bioregulators.” Within this emerging domain, the synthetic heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) stands as a paragon of rational drug design. Developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, Semax represents a bridge between the endogenous endocrine system and therapeutic intervention, utilizing the structural scaffold of the adrenocorticotropic hormone (ACTH) to exert potent neuroprotective and nootropic effects.1

As a research scientist whose primary focus lies in the intricate machinery of mitochondrial bioenergetics and cellular metabolism, the investigation of Semax offers a particularly compelling narrative. The brain, despite comprising only 2% of total body mass, consumes approximately 20% of the body’s basal oxygen, a demand met almost exclusively by mitochondrial oxidative phosphorylation. Pathologies such as ischemic stroke, traumatic brain injury (TBI), and neurodegenerative decline are fundamentally crises of bioenergetics—failures of the mitochondria to sustain membrane potential and ionic homeostasis under stress. Semax appears to intervene precisely at this metabolic nexus, not merely as a stimulant, but as a modulator of the cellular stress response.4

This report aims to provide an exhaustive, expert-level analysis of Semax. It synthesizes decades of data, ranging from fundamental biochemical characterization and transcriptomic profiling to clinical trials in ischemic stroke and optic nerve atrophy. We will dissect the peptide’s ability to remodel the genomic landscape of neurons, upregulate critical neurotrophins like Brain-Derived Neurotrophic Factor (BDNF), and modulate the brain’s intrinsic connectivity networks. Furthermore, we will critically evaluate the translational potential of this peptide for human performance optimization, scrutinizing the theoretical basis for its use in conditions like Attention Deficit Hyperactivity Disorder (ADHD) and depression against the backdrop of anecdotal evidence and rigorous safety profiling.

2. Pharmacokinetics

2.1 The Rational Design of Semax

The genesis of Semax lies in the study of the adrenocorticotropic hormone (ACTH), a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. Early research in the mid-20th century identified that ACTH possessed potent behavioral effects independent of its steroidogenic activity (stimulation of cortisol release). Specifically, the N-terminal fragment, ACTH(4-10) (Met-Glu-His-Phe-Arg-Trp-Gly), was found to facilitate learning and memory in animal models. However, the native fragment suffered from a fatal flaw for clinical application: extreme instability. Native peptides are rapidly degraded by serum peptidases, rendering their biological half-life too short to sustain therapeutic effects.2

Semax was engineered to overcome this limitation through a specific structural modification: the replacement of the C-terminal sequence of ACTH(4-10) with the tripeptide Pro-Gly-Pro (PGP). The resulting sequence, Met-Glu-His-Phe-Pro-Gly-Pro, confers remarkable stability. The inclusion of proline, an imino acid with a rigid cyclic structure, induces conformational constraints that protect the peptide bond from enzymatic hydrolysis. This modification effectively extends the duration of the peptide’s biological activity from minutes to 20-24 hours following a single administration, despite a plasma half-life that remains relatively transient.7 This dissociation between plasma half-life and biological effect duration suggests that Semax acts as a trigger, initiating sustained intracellular signaling cascades and genomic alterations that persist long after the parent molecule has been metabolized.

2.2 PGP Tripeptide

It is critical to recognize that the Pro-Gly-Pro (PGP) moiety is not merely an inert protective cap. Independent research into glyprolines (proline-containing peptides) suggests that PGP itself possesses intrinsic biological activity. PGP has been shown to exert protective effects on gastric mucosa and may contribute to the peptide’s overall anticoagulatory and immunomodulatory profile.9 Thus, Semax should be viewed as a hybrid molecule where the N-terminal ACTH fragment provides specific melanocortin-like neurotropic signaling, while the C-terminal PGP enhances stability and contributes to metabolic regulation and cytoprotection.11

2.3 Blood-Brain Barrier Transport and Bioavailability

The efficacy of any neurotropic agent is contingent upon its ability to cross the blood-brain barrier (BBB). Semax is predominantly administered via the intranasal route. This route is strategically advantageous for neuropeptides as it allows for direct transport into the central nervous system (CNS) via the olfactory and trigeminal nerve pathways, bypassing the BBB and hepatic first-pass metabolism.

Studies utilizing radiolabeled Semax have confirmed its rapid penetration into the brain. Within minutes of intranasal administration, the peptide can be detected in cerebrospinal fluid and specific brain structures.5 The binding of Semax in the brain is not uniform; specific binding sites have been identified in the basal forebrain and hippocampus, regions critical for memory and cognitive function.6 The binding kinetics are specific, reversible, and calcium-dependent, suggesting interaction with a distinct receptor system rather than non-specific membrane intercalation.

3. Mechanisms of Action

Semax operates through a pleiotropic mechanism, influencing the CNS at multiple levels: from the reception of membrane signals to the remodeling of chromatin and the modulation of neurotransmitter turnover.

3.1 Neurotrophin Regulation: The BDNF/TrkB Axis

The most robustly documented mechanism of Semax is its ability to stimulate the synthesis of neurotrophins, specifically Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF). These proteins are pivotal for neuronal survival, differentiation, and synaptic plasticity.

3.1.1 Brain-Derived Neurotrophic Factor (BDNF)

BDNF is arguably the most critical molecule for neuroplasticity and long-term potentiation (LTP). Reduced BDNF levels are implicated in the pathophysiology of depression, Alzheimer’s disease, and post-stroke neuronal death. Semax administration elicits a rapid and sustained increase in BDNF protein levels and mRNA expression. In rat models, a single intranasal dose resulted in significantly elevated BDNF levels in the basal forebrain, hippocampus, and frontal cortex within 3 hours.1

Crucially, Semax not only upregulates the ligand (BDNF) but also its high-affinity receptor, Tropomyosin receptor kinase B (TrkB).7 This simultaneous upregulation sensitizes neurons to neurotrophic signaling, creating a feed-forward loop of neuroprotection. The activation of the TrkB receptor triggers downstream signaling pathways, including the MAPK/ERK and PI3K/Akt pathways, which promote cell survival and protein synthesis required for synaptic strengthening.

3.1.2 Nerve Growth Factor (NGF)

While the effect on BDNF is rapid, the modulation of NGF appears to be more complex and temporally distinct. In the frontal cortex and hippocampus, NGF expression increases approximately 8 hours after Semax administration.1 This delayed response suggests that NGF upregulation may be a secondary effect, perhaps downstream of initial BDNF signaling or other immediate-early gene activations. The differential regulation of these neurotrophins allows Semax to support both immediate synaptic function and long-term neuronal structural integrity.15

3.2 Transcriptomic Modulation

The advent of high-throughput RNA sequencing (RNA-Seq) has allowed researchers to map the global gene expression changes induced by Semax. These studies have revealed that Semax acts as a profound modulator of the transcriptome, particularly under conditions of ischemic stress.

3.2.1 Immune System Regulation and Inflammation

Unexpectedly, genome-wide expression analysis in rat models of middle cerebral artery occlusion (MCAO) revealed that the largest cluster of genes modulated by Semax belongs to the immune system. Semax treatment significantly upregulates genes encoding immunoglobulins, chemokines, and cytokine receptors.4

At first glance, upregulating immune genes during a stroke might seem counterintuitive, as inflammation is often viewed as damaging. However, the specific pattern of modulation suggests that Semax promotes a protective, adaptive immune response while suppressing deleterious inflammation. Specifically, Semax has been observed to suppress the expression of pro-inflammatory cytokines such as Il1b, Il6, Tnfa, and Cxcl2 24 hours after ischemia.16 By dampening this “cytokine storm” while enhancing genes involved in immune cell migration and debris clearance, Semax effectively manages the sterile inflammation that contributes to reperfusion injury and secondary neuronal death.

3.2.2 Vascular and Angiogenic Gene Expression

Semax also exerts a potent influence on the vascular system at the genetic level. It modulates the expression of the VEGF gene family (Vegfa, Vegfb, Vegfc, Vegfd) and their receptors (Vegfr1, Vegfr2).17 Ischemia typically suppresses the expression of these angiogenic factors. Semax treatment reverses this suppression, normalizing or even enhancing the expression of Vegfb and Vegfd. This promotes angiogenesis and the maintenance of the microvasculature, ensuring that the metabolic demands of regenerating neurons can be met by adequate perfusion.

3.2.3 Neurotransmitter Gene Expression

Under ischemic conditions, the brain typically downregulates genes involved in neurotransmission, leading to functional silence. Semax treatment has been shown to counteract this suppression, maintaining the expression of genes related to synaptic transmission.8 This preservation of the “neurotransmitter transcriptome” likely underlies the rapid functional recovery observed in clinical stroke trials, as neural networks remain primed for activity rather than entering a dormant or apoptotic state.

3.3 Mitochondrial Bioenergetics and Oxidative Stress

As a scientist specializing in metabolism, the interaction between Semax and mitochondrial function is of particular significance.

3.3.1 PGC-1α Induction

Recent studies have identified that Semax induces the expression of Ppargc1a (PGC-1α) in penumbral neurons.5 PGC-1α is the master transcriptional coactivator regulating mitochondrial biogenesis and oxidative metabolism. By upregulating PGC-1α, Semax enhances the cell’s capacity to generate ATP and manage energy deficits. This is a critical neuroprotective mechanism, as mitochondrial failure is the precipitating event in necrotic cell death following ischemia.

3.3.2 Calcium Homeostasis and Oxidative Defense

Semax protects neurons from glutamate excitotoxicity, a process driven by massive calcium influx and subsequent mitochondrial overload. In cerebellar granule cell cultures, Semax delayed the deregulation of calcium homeostasis and prevented the collapse of mitochondrial membrane potential.10 Furthermore, Semax enhances the activity of endogenous antioxidant enzymes, including superoxide dismutase (SOD) and catalase, thereby reducing the levels of toxic lipid peroxidation products like malondialdehyde.19 This dual action—stabilizing calcium handling and bolstering antioxidant defenses—preserves mitochondrial integrity during lethal stress.

3.3.3 Interaction with Heavy Metals and Amyloid

Semax has also demonstrated the ability to interact with copper ions and amyloid-beta (Aβ) peptides. It can prevent the formation of Aβ-Cu2+ complexes and inhibit the aggregation of amyloid fibrils, a hallmark of Alzheimer’s pathology.20 This suggests a potential role in preventing the metal-catalyzed oxidative stress associated with neurodegeneration.

3.4 Neurotransmitter Systems

Semax modulates the dopaminergic and serotonergic systems in a unique manner that distinguishes it from classical psychostimulants like amphetamines.

Dopamine: Semax does not tonically increase extracellular dopamine levels in the striatum when administered alone.1 This is a crucial safety feature, as it minimizes the risk of oxidative stress associated with dopamine metabolism and reduces the likelihood of receptor downregulation or addiction. However, Semax dramatically potentiates the dopamine release induced by d-amphetamine.9 This suggests that Semax acts as a positive modulator, enhancing the efficiency of dopaminergic signaling on demand when the system is activated, rather than forcing release indiscriminately.
Serotonin: In contrast to its conditional effect on dopamine, Semax appears to directly increase serotonin turnover. Studies show elevated levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and hypothalamus.1 This activation of the serotonergic system correlates with the peptide’s observed anxiolytic and antidepressant-like behavioral effects.

4. Preclinical Evidence

The efficacy of Semax has been rigorously tested in various mammalian models, providing a foundation for its clinical use.

4.1 Cognitive Enhancement and Memory

In healthy rats, Semax consistently facilitates learning and memory consolidation. It accelerates the acquisition of conditioned passive avoidance reactions and improves performance in spatial memory tasks like the Morris water maze.1 The nootropic effect is rapid, often observable within hours, and is distinct from the non-specific arousal caused by stimulants. Importantly, Semax has been shown to restore memory function in animals subjected to diverse amnestic insults, including hypoxia, ethanol toxicity, and anticholinergic drugs, demonstrating a restorative capacity for cognitive networks.25

4.2 Ischemic Stroke Models

The neuroprotective effects of Semax are most profoundly demonstrated in models of focal cerebral ischemia (stroke).

Infarct Reduction: In photothrombotic and MCAO models, Semax treatment significantly reduces the volume of the infarct core and the surrounding penumbra.5
Functional Recovery: Rats treated with Semax exhibit accelerated recovery of sensorimotor functions and reduced neurological deficit scores compared to controls.4
Mechanisms: The protection is attributed to the suppression of inflammatory genes (Il1b, Tnfa), upregulation of neurotrophins (Bdnf), and preservation of the blood-brain barrier integrity through MMP-9 downregulation in the cortex.26

4.3 Stress and Developmental Disorders

Semax exhibits significant adaptogenic properties. In models of chronic unpredictable stress (CUS), Semax prevented the development of depressive-like behaviors such as anhedonia (measured by sucrose preference) and behavioral despair.27 Furthermore, in a model of developmental injury where neonatal rats were exposed to SSRIs (fluvoxamine), resulting in long-term emotional and cognitive deficits, subsequent Semax treatment normalized behavior and monoamine levels.28 This suggests that Semax can correct maladaptive neurodevelopmental trajectories, potentially via the restoration of proper serotonergic signaling and BDNF support.

5. Clinical Applications and Human Trials

While Semax is not approved by the FDA, it has been a registered pharmaceutical in Russia and Ukraine for decades. The clinical data from these regions is extensive, particularly regarding stroke and neurological injury.

5.1 Ischemic Stroke Therapy

Semax is included in the Russian List of Vital & Essential Drugs and is standard of care for ischemic stroke in many Eastern European hospitals.

Trial Data: In a study of 110 patients with ischemic stroke, Semax treatment (high dose, e.g., 12-18 mg/day or equivalent high-concentration drops) resulted in significantly improved scores on the Barthel Index (a measure of performance in activities of daily living) and the Scandinavian Stroke Scale.16
Biomarkers: Patients receiving Semax showed sustained elevations in plasma BDNF levels, which correlated positively with the speed and extent of functional recovery.30
Timing: The efficacy was highest when Semax was initiated early (within the acute phase) and combined with rehabilitation, emphasizing its role in priming the brain for recovery.

5.2 Optic Nerve Disease and Glaucoma

Semax is utilized in ophthalmology to treat optic nerve atrophy and glaucomatous optic neuropathy.

Clinical Outcomes: Studies report that Semax therapy (administered intranasally or via endonasal electrophoresis) improves visual acuity, expands the visual field, and increases the electrical sensitivity of the optic nerve.31
Mechanism: The benefit is attributed to the protection of retinal ganglion cells from apoptosis and the improvement of microcirculation in the retina and optic nerve head.5

5.3 Cognitive Enhancement

In a controlled study involving healthy male operators (aged 20-25), Semax administration (0.25-1.0 mg) improved attention, short-term memory, and visual-motor coordination. The number of errors in proofreading tasks decreased, and EEG analysis revealed increased alpha-activity, a marker of relaxed alertness and efficient information processing.34 These findings validate the classification of Semax as a true “nootropic”—a substance that enhances cognition in healthy individuals, not just those with deficits.

5.4 Modulation of the Default Mode Network (DMN)

A pivotal study by Lebedeva et al. (2018) used resting-state fMRI to investigate the effects of Semax on the healthy human brain. Intranasal administration increased the volume of the rostral subcomponent of the Default Mode Network (DMN), specifically in the medial frontal cortex.1 The DMN is a network of interacting brain regions active when a person is not focused on the outside world (daydreaming, memory retrieval, envisioning the future). Strengthening connectivity within this network may underlie Semax’s effects on memory consolidation and self-referential processing.

6. Potential Applications

Given the robust mechanistic data, there is significant interest in the off-label use of Semax for conditions not yet fully covered by clinical trials. The following sections outline theoretical applications based on pharmacological principles and anecdotal user reports from online communities.

6.1 ADHD and Executive Function

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by deficits in dopamine and norepinephrine signaling in the prefrontal cortex.

Potential Rationale: Semax modulates dopamine turnover and potentiates dopaminergic signaling without causing the depletion of vesicular stores seen with amphetamines. By upregulating BDNF, it may also address the underlying neurodevelopmental lag in cortical maturation associated with ADHD.37
Anecdotal Evidence: Users on platforms discussing nootropics frequently report that Semax provides “clean” stimulation, improving task initiation and focus without the jitteriness, anxiety, or “crash” associated with traditional stimulants like Adderall or Ritalin.39 Many users prefer it for its ability to sustain executive function during periods of high cognitive demand.

6.2 Depression and Anhedonia

Anhedonia, the inability to feel pleasure, is a core symptom of depression often resistant to SSRIs, linked to dopaminergic dysfunction.

Potential Rationale: Semax’s ability to increase striatal serotonin turnover and restore sucrose preference in stressed rats suggests antidepressant potential. Its induction of BDNF is also relevant, as the “neurotrophic hypothesis of depression” posits that increasing BDNF is key to the therapeutic action of antidepressants.13
Anecdotal Evidence: Reports suggest Semax can exert a mood-stabilizing effect, lifting the “fog” of depression and improving motivation. Some users describe it as subtle but profound in restoring the “color” to emotional life, possibly via its modulation of the DMN and reward circuitry.41

6.3 Metabolic Optimization

Potential Rationale: The induction of PGC-1α by Semax suggests it could enhance systemic metabolic efficiency. PGC-1α drives mitochondrial biogenesis and oxidative capacity. Theoretically, Semax could aid in conditions of metabolic syndrome or fatigue by improving cellular energy handling.5 This connects the peptide’s central effects with the peripheral metabolic role of the melanocortin system.

7. Safety Profile, Concerns, and Contraindications

While Semax has a favorable safety profile compared to many psychotropic drugs, it is a potent biological agent with specific contraindications and theoretical risks.

7.1 Contraindications

Pregnancy and Lactation: Semax is strictly contraindicated during pregnancy and breastfeeding. As a peptide that modulates critical growth factors (BDNF, NGF) and interacts with the ACTH/melanocortin axis, it poses significant theoretical risks to fetal neurodevelopment and hormonal balance. No safety data exists for this population, and the potential for teratogenicity or developmental disruption is too high to risk.7
Acute Psychiatric Disorders: Patients with acute psychosis, mania, or severe anxiety attacks should avoid Semax. Its stimulatory effects on the CNS and dopaminergic/serotonergic modulation could exacerbate these conditions.12
History of Convulsions: Although some animal data suggests anticonvulsant effects, clinical guidelines often list a history of convulsions or epilepsy as a contraindication. This caution likely stems from the peptide’s ability to alter neuronal excitability and calcium signaling.44

7.2 Adverse Effects

Common: Mild irritation of the nasal mucosa, dryness, or a stinging sensation immediately after administration.
Occasional: Insomnia or sleep disturbances if administered late in the day, due to increased vigilance and arousal.42
Rare: Transient headaches, slight increases in blood glucose levels (observed in ~7.4% of diabetic patients in some studies).1

7.3 The “Hair Loss” Controversy: A Mechanistic Hypothesis

A persistent topic in online discussion communities is the potential for Semax to cause hair loss. While not a listed side effect in official Russian literature, a deep dive into molecular biology offers a plausible mechanism.

The Mechanism: Brain-Derived Neurotrophic Factor (BDNF) is a known catagen inducer in hair follicles. In human hair follicle cultures, high levels of BDNF inhibit hair shaft elongation and trigger premature entry into the catagen (regression) phase. This effect is mediated by the TrkB receptor on keratinocytes, which upregulates Transforming Growth Factor beta 2 (TGF-β2), a powerful signal for follicle regression.45
Implication: Since Semax significantly and systemically upregulates BDNF, it is theoretically possible that in individuals with high sensitivity (e.g., high scalp TrkB expression), chronic use could accelerate the transition of hair follicles into the shedding phase (telogen effluvium) or exacerbate androgenetic alopecia. This represents a classic “second-order” side effect where a beneficial central mechanism (neuroprotection) becomes a deleterious peripheral signal.

7.4 Drug Interactions

Stimulants: Semax potentiates the effects of dopaminergic stimulants (e.g., amphetamines). Concomitant use requires extreme caution as it may lead to overstimulation, anxiety, or hypertension.9
SSRIs/MAOIs: Because Semax increases serotonin turnover, there is a theoretical risk of serotonin syndrome if combined with high doses of SSRIs or MAOIs, although this has not been widely reported in clinical literature. Caution is advised.48

8. Dosing and Administration Protocols

Semax is available in two primary concentrations, reflecting its distinct indications. It is administered strictly intranasally.

8.1 Semax 0.1% (Cognitive/Nootropic)

Indication: Cognitive enhancement, memory improvement, mental fatigue, mild cerebrovascular insufficiency.
Protocol: Typically 2-3 drops in each nostril, 2-3 times daily.
Cycle: A standard course lasts 10-14 days. It is recommended to cycle the drug (e.g., 2-4 courses per year) to prevent receptor desensitization and maintain efficacy.44

8.2 Semax 1.0% (Clinical/Stroke)

Indication: Acute ischemic stroke, transient ischemic attack (TIA), severe TBI.
Protocol: Much higher doses are used. A typical regimen might involve 2-3 drops per nostril every 3-4 hours for 10 days, initiated as soon as possible after injury.50
Note: The 1.0% solution is 10 times more concentrated than the 0.1% version and is generally reserved for acute medical crises under physician supervision.

9. Conclusion

Semax represents a sophisticated pharmacological tool that transcends the simplistic categorization of “stimulant” or “nootropic.” Its primary value lies in its ability to enhance the brain’s homeostatic resilience. By modulating the transcriptome to suppress deleterious inflammation, upregulating intrinsic repair systems (BDNF, VEGF), and optimizing mitochondrial bioenergetics (PGC-1α), Semax acts as a buffer against metabolic and ischemic stress.

For the researcher and clinician, Semax offers a unique profile: it enhances dopaminergic signaling without the neurotoxicity of amphetamines; it combats depression-like states by restoring neurotrophic support; and it aids in stroke recovery by remodeling the gene expression landscape of the injured brain. However, this potency comes with theoretical risks, particularly regarding peripheral BDNF effects (hair loss) and the strict necessity to avoid use during pregnancy.

Ultimately, Semax serves as a powerful proof-of-concept for peptide bioregulators. Its application in human health, particularly for off-label cognitive optimization, is supported by a wealth of mechanistic data but necessitates a nuanced understanding of its biological actions to maximize benefits while mitigating risks.

Table 1: Comparative Pharmacodynamics of Semax vs. Traditional Psychostimulants

Feature	Semax (ACTH 4-10 Analogue)	Amphetamines/Psychostimulants
Mechanism	Receptor modulation (MC4/5); Gene expression (BDNF/NGF); Transcriptomic remodeling 1	Direct release of monoamines; Reuptake inhibition; VMAT2 inhibition 25
Dopamine Effect	Modulatory: Potentiates release only upon stimulation; No tonic increase at rest 9	Forced Release: Depletes vesicular stores; Increases tonic extracellular levels 51
Neuroprotection	High: Reduces excitotoxicity, oxidative stress, and inflammation 4	Negative: Potential for oxidative stress, excitotoxicity, and terminal damage at high doses
Metabolic Impact	Enhances mitochondrial biogenesis (PGC-1α); Antioxidant upregulation 5	Increases metabolic rate; Induces catabolic stress and ROS production
Side Effects	Minimal (nasal irritation); Theoretical hair loss (BDNF mechanism) 45	Insomnia, anxiety, hypertension, appetite suppression, addiction risk
Dependency	None observed; No withdrawal syndrome reported 5	High potential for tolerance, dependence, and withdrawal

Table 2: Transcriptomic and Protein Changes Induced by Semax in Ischemic Models

Gene/Protein Target	Effect of Ischemia (Untreated)	Effect of Semax Treatment	Functional Implication
Neurotrophins (Bdnf, Ngf)	Suppressed or delayed	Significant Upregulation (Rapid & Sustained) 6	Promotes neuronal survival, synaptic plasticity, and repair.
Pro-inflammatory Cytokines (Il1b, Il6, Tnfa)	Massively Upregulated	Significant Downregulation 16	Reduces neuroinflammation, reperfusion injury, and secondary cell death.
Vascular Factors (Vegfa, Vegfb)	Variable/Suppressed	Upregulated/Normalized 17	Supports angiogenesis and maintains microcirculation in the penumbra.
Mitochondrial Regulators (Ppargc1a / PGC-1α)	Downregulated	Upregulated 5	Preserves mitochondrial biogenesis and cellular energy production.
Matrix Metalloproteinases (Mmp9)	Upregulated (Disrupts BBB)	Downregulated (in cortex) 26	Preserves blood-brain barrier integrity; reduces edema.
Immunoglobulins & Chemokines	Dysregulated	Modulated (Specific clusters enhanced) 4	Orchestrates adaptive immune response and debris clearance.

Table 3: Clinical Dosing Guidelines (Based on Russian Protocols)

Indication	Concentration	Typical Dosage per Administration	Frequency	Duration & Cycle
Cognitive Enhancement / Mental Fatigue	0.1%	2-3 drops / nostril	2x daily (Morning/Afternoon)	10-14 days; repeat 2-4x per year 50
Mild Memory Impairment	0.1%	2-3 drops / nostril	2-3x daily	10-14 days 44
Ischemic Stroke (Acute Phase)	1.0%	2-3 drops / nostril	3-4x daily (every 3-4h)	10 days; start immediately upon diagnosis 50
Optic Nerve Atrophy / Glaucoma	0.1% or 1.0%	Dose varies (often via electrophoresis)	Daily	10 days per course 33
Post-Stroke Rehabilitation	0.1%	2-3 drops / nostril	2-3x daily	10-14 days 30

Note: 1 drop of 0.1% solution typically contains ~50 mcg of active peptide. 1 drop of 1.0% solution contains ~500 mcg. Medical supervision is recommended for all therapeutic uses.