Neuropeptides & Cognitive Function

Short regulatory peptides produced by the brain, pituitary, and immune system converge on overlapping signaling networks that govern synaptic plasticity, anxiety, sleep architecture, and neuronal survival. Three research compounds, Semax, Selank, and DSIP, illustrate how structurally distinct neuropeptides can engage complementary receptor systems to amplify a shared set of plasticity effectors: BDNF, TrkB, CREB, ERK1/2, and Akt. Understanding this pathway requires tracing each peptide’s receptor entry point through the downstream cascades that ultimately regulate gene expression in hippocampal and cortical neurons. The same network is disrupted in anxiety disorders, post-ischemic injury, and stress-related cognitive impairment, making it a coherent target for research-grade neuropeptide pharmacology.

Pathway Components

Upstream Ligands

Semax

Semax is a synthetic heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP). It was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences as a metabolically stable analogue of ACTH residues 4-10. The C-terminal Pro-Gly-Pro tripeptide slows aminopeptidase degradation without eliminating CNS activity; the PGP sequence independently upregulates neurotrophin receptor gene expression in ischemia models (PMID: 19633950). Unlike full-length ACTH, Semax carries no steroidogenic activity: it does not activate MC2R in the adrenal cortex and produces no change in plasma cortisol (PMID: 16996037).

Selank

Selank is a synthetic heptapeptide with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP), derived from tuftsin (residues 289-292 of the IgG heavy chain Fc region, gene IGHG1) with a C-terminal Pro-Gly-Pro extension. Selank is registered by the Russian Ministry of Health as a 0.15% intranasal formulation for generalized anxiety disorder. Preclinical pharmacokinetic studies using tritiated Semax established high-affinity binding sites in the rat basal forebrain with Kd of 2.4 nM and Bmax of 33.5 fmol/mg protein (PMID: 16635254), and analogous binding data have been reported for Selank in cortical membrane fractions.

DSIP

DSIP (delta sleep-inducing peptide) is a nonapeptide with the sequence Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu (WAGGDASGE), first isolated in 1974 from cerebral venous blood of electrically stimulated sleeping rabbits by Monnier and Schoenenberger (PMID: 568769). Its molecular weight is approximately 850 Da and it is amphiphilic, facilitating blood-brain barrier transit. Uniquely among characterized neuropeptides, no encoding gene, biosynthetic precursor, or dedicated high-affinity receptor has been cloned or crystallized for DSIP. DSIP-like immunoreactivity is distributed in the hypothalamus, limbic system, anterior pituitary, gut, adrenals, and gonads, and exhibits a circadian plasma rhythm abolished by constant light exposure.

Primary Receptors

MC4R (Melanocortin-4 Receptor)

Gene: MC4R; UniProt: P32245. MC4R is a 332-amino-acid class A GPCR expressed at high levels in the hippocampus, prefrontal cortex, hypothalamus, and amygdala. It couples through Galpha-s to stimulate adenylyl cyclase and raise intracellular cAMP. Endogenous agonists are POMC-derived peptides: alpha-MSH, beta-MSH, gamma-MSH, and full-length ACTH. Semax acts as a partial agonist at MC4R and the closely related MC3R. Calcium coordinates ligand binding through residues E100, D122, and D126 in the transmembrane bundle.

In hippocampal CA1 neurons, MC4R activation increases mature dendritic spine density and drives AMPA receptor subunit GluA1 (GRIA1, UniProt: P42261) surface expression via a PKA-dependent mechanism: MC4R -> Galpha-s -> adenylyl cyclase -> cAMP -> PKA -> GluA1 Ser845 phosphorylation -> AMPA receptor membrane insertion -> enhanced EPSP amplitude and lower LTP induction threshold. PKA blockade with H-89 or Rp-cAMPS completely abolishes MC4R-mediated LTP enhancement (PMID: 23303927).

The endogenous antagonist AGRP (agouti-related peptide) competes with alpha-MSH at MC4R, and MRAP2 (melanocortin receptor accessory protein 2) increases MC4R ligand sensitivity and amplifies cAMP generation. See Melanocortin Axis for the full POMC/ACTH/MC receptor network.

GABA-A Receptor (Selank Target)

Multiple subunits; canonical benzodiazepine-sensitive subunit: GABRA1, UniProt: P14867. GABA-A receptors are pentameric ligand-gated chloride channels. Selank does not act as a direct GABA-A agonist. Instead, gene-expression profiling in rat frontal cortex after intranasal Selank administration showed alteration of 45 of 84 surveyed GABA-related genes at the one-hour time point (PMID: 26924987). The most pronounced single changes were a 20-fold decrease in GABRE (epsilon subunit) and a 20-fold decrease in GABRQ (theta subunit) mRNA. GABRB3 (beta-3 subunit) mRNA increased 1.6-fold. GAD1 (glutamate decarboxylase 67, the GABA synthesis enzyme) was also upregulated, suggesting Selank increases endogenous GABA production. This transcriptional profile is consistent with allosteric remodeling of GABA-A receptor composition rather than direct chloride-channel agonism.

For DSIP, pharmacological evidence indicates it potentiates GABA-activated chloride currents in hippocampal and cerebellar neurons through a distinct mechanism from benzodiazepines, and blocks NMDA-activated currents in cortical preparations.

NMDA Receptor (DSIP Target)

Key subunits: GRIN2A (UniProt: Q12879) and GRIN2B (UniProt: Q13224). NMDA receptors are heteromeric ionotropic glutamate receptors that require both ligand binding (glutamate plus glycine) and membrane depolarization for channel opening. DSIP dampens NMDA-activated currents in cortical neurons, contributing to its anticonvulsant properties and reducing excitotoxic calcium influx under ischemic conditions. The naloxone sensitivity of DSIP-induced slow-wave sleep in the median thalamus indicates concurrent engagement of endogenous opioid circuits downstream of its NMDA-modulating activity.

Enkephalinase / Neprilysin (MME)

Gene: MME; UniProt: P08473. Neprilysin (neutral endopeptidase, enkephalinase) is the primary enzyme responsible for degrading endogenous enkephalins at the synaptic cleft. Both Semax and Selank inhibit enkephalinase activity; Selank is more potent than the classical peptidase inhibitors bacitracin and puromycin in this assay (Zozulya et al.). By slowing Met-enkephalin and Leu-enkephalin (encoded by PENK, UniProt: P01210) degradation, these peptides raise tonic activation of mu-opioid receptors (OPRM1, UniProt: P35372) and delta-opioid receptors (OPRD1, UniProt: P41143) without directly binding them. DSIP, in contrast, stimulates calcium-dependent Met-enkephalin release from rat lower brainstem slices through an exocytotic mechanism (PMID: 2706459).

Downstream Signaling Cascades

cAMP / PKA / CREB (Semax Primary Cascade)

MC4R/Galpha-s activation by Semax raises cAMP, which activates PKA (catalytic subunit PRKACA, UniProt: P17612). PKA phosphorylates two critical substrates relevant to cognition:

1. CREB (CREB1, UniProt: P16220) at Ser133. Phospho-CREB recruits the co-activator CBP/p300 and drives transcription of genes under cAMP-response element (CRE) promoter control, principally BDNF (exon III and IV promoters) and NGF. This transcriptional response is detectable within 30-90 minutes of Semax administration.
2. GluA1 at Ser845. Ser845 phosphorylation promotes exocytotic insertion of GluA1-containing AMPA receptors from intracellular recycling endosomes to the postsynaptic density, lowering the threshold for LTP induction (PMID: 23303927).

cAMP also activates the EPAC (Exchange Protein directly Activated by cAMP) pathway, which signals through Rap1 and B-Raf to activate MEK1/2 independently of Ras, providing a second route to ERK1/2 phosphorylation.

BDNF / TrkB / MAPK-ERK Cascade

The cAMP/CREB-driven increase in BDNF (BDNF, UniProt: P23560) is the best-characterized molecular consequence of Semax. Single intranasal Semax at 50 microg/kg in rats produced a 3-fold increase in hippocampal BDNF mRNA (exon III), a 2-fold increase in TrkB (NTRK2, UniProt: Q16620) mRNA, a 1.4-fold increase in BDNF protein, and a 1.6-fold increase in TrkB tyrosine phosphorylation within three hours (PMID: 16996037). In the basal forebrain, BDNF protein was elevated within 3 hours of intranasal Semax at both 50 and 250 microg/kg (PMID: 16635254).

Secreted BDNF binds TrkB, which dimerizes and trans-autophosphorylates at five tyrosine residues. The key downstream branches from NTRK2/TrkB are:

MAPK/ERK arm: pTyr516 recruits SHC1, which assembles a GRB2/SOS complex activating Ras. Ras-GTP activates RAF1/BRAF, which phosphorylates MEK1/2 (MAP2K1/MAP2K2), which phosphorylates ERK1/2 (MAPK3/MAPK1, UniProt: P27361/P28482). Nuclear ERK1/2 phosphorylates ELK1, RSK2, and CREB (Ser133), driving immediate-early gene expression programs including BDNF itself, FOS, and EGR1. This creates a positive feedback loop: Semax -> cAMP/PKA -> BDNF -> TrkB/ERK -> more BDNF.

PI3K/Akt arm: FRS2 and SH2B1 adaptors downstream of pTyr516 activate PI3K (catalytic subunit PIK3CA), generating PIP3. PDK1 phosphorylates Akt at T308, and mTORC2 completes activation at S473. Active Akt (AKT1, UniProt: P31749) phosphorylates BAD and FOXO transcription factors to suppress apoptosis, and activates mTORC1 to drive protein synthesis for dendritic spine growth and synaptogenesis. See PI3K/Akt Pathway for full Akt substrate details.

PLCgamma/CaMKII arm: pTyr817 recruits PLCG1 (PLCG1, UniProt: P19174). PLCgamma cleaves PIP2 into IP3 and DAG. IP3 triggers ER calcium release. The calcium transient activates CaMKII (CAMK2A, UniProt: Q9UQM7), which phosphorylates GluA1 at Ser831, increasing single-channel conductance and contributing to LTP expression at the synapse level.

In ischemia models, Semax produced coordinate upregulation of BDNF, NGF (NGF, UniProt: P01138), NT-3, TrkA (NTRK1, UniProt: P04629), and TrkC (NTRK3, UniProt: Q16288) mRNA in the ischemic cortex within 3-72 hours of permanent middle cerebral artery occlusion (PMID: 19633950). Co-expression of neurotrophins alongside their cognate high-affinity receptors maximizes autocrine and paracrine survival signaling in the peri-infarct penumbra.

Selank-Specific Effectors

Beyond GABA-A modulation and enkephalinase inhibition, two Selank-specific gene expression findings are mechanistically significant:

DRD3 upregulation: Dopamine receptor D3 (DRD3, UniProt: P35462) mRNA increased 3.4-fold in rat frontal cortex at one hour after intranasal Selank (PMID: 26924987). DRD3 is a Gi/Go-coupled GPCR expressed in the nucleus accumbens, ventral striatum, islands of Calleja, and limbic areas. Its upregulation by Selank implicates mesolimbic dopamine circuit modulation in the anxiolytic and cognitive effects. DRD5 was also upregulated; DRD5 couples through Gs and mediates hippocampal LTP and memory formation.

Orexin/hypocretin suppression: HCRT (hypocretin/orexin prepropeptide, UniProt: O43612) mRNA decreased 25-fold at one hour after Selank, and 50-fold after GABA, in the same frontal cortex study. HCRTR2 (orexin receptor 2) was co-downregulated. Orexin is a potent pro-arousal and anxiety-amplifying neuropeptide; its suppression by Selank may explain the compound’s non-sedating anxiolytic profile: reduced arousal tone without the sedation seen with direct GABA-A agonists.

BDNF normalization: Selank elevated hippocampal BDNF mRNA in intact rats (Inozemtseva et al., 2008) and prevented pathological BDNF elevation in ethanol-exposed rats while simultaneously improving cognitive performance, suggesting state-dependent normalization rather than unconditional upregulation (PMID: 31625062). In a chronic unpredictable stress model, Selank increased hippocampal BDNF protein by approximately 27%.

DSIP-Specific Effectors

HPA axis suppression: DSIP reduces basal ACTH/corticotropin release, blocks CRH-driven cortisol secretion, and reduced plasma corticosterone by approximately 30% in rat studies. Reduced cortisol is relevant to cognition because sustained glucocorticoid receptor (GR) activation suppresses BDNF exon IV promoter activity in the hippocampus, reduces hippocampal neurogenesis, and impairs LTP. DSIP-mediated HPA normalization therefore indirectly supports the same BDNF-TrkB-MAPK axis that Semax activates directly.

Neuroendocrine coordination: DSIP stimulates LH, GHRH, and GH secretion while inhibiting somatostatin. It modulates pineal N-acetyltransferase (AANAT, UniProt: Q16613) activity, the rate-limiting enzyme in melatonin synthesis, linking DSIP to circadian rhythm regulation alongside its acute sleep-inducing properties.

Mitochondrial bioenergetics: DSIP pretreatment at 120 microg/kg (i.p.) in rats completely inhibited hypoxia-induced reduction of mitochondrial respiratory chain activity and modulated MAO-A (MAOA, UniProt: P21397), hexokinase, creatine kinase, and malate dehydrogenase activities under oxidative stress conditions (PMID: 7628639). The net effect is preservation of neuronal ATP production during metabolic insults.

GILZ homology and MAPK interaction: DSIP shares structural homology with glucocorticoid-induced leucine zipper (GILZ, TSC22D3, UniProt: O14967). GILZ suppresses Raf-1 activation, blocking MEK-ERK phosphorylation. This homology suggests DSIP may modulate the threshold of stress-activated MAPK signaling independently of its neuroendocrine effects. See MAPK Cascade for the Raf-MEK-ERK network context.

Signal Flow Diagram

The flowchart maps each peptide from its entry receptor through its primary signaling cascades to shared plasticity effectors and physiological outputs.

flowchart TD
    subgraph Ligands["Neuropeptide Ligands"]
        SX["Semax (MEHFPGP)\nACTH 4-10 analogue"]
        SE["Selank (TKPRPGP)\nTuftsin analogue"]
        DS["DSIP (WAGGDASGE)\nNonapeptide, no encoding gene"]
    end

    subgraph Receptors["Primary Receptors"]
        MC4R["MC4R (P32245)\nGalpha-s GPCR\nHippocampus / Cortex"]
        GABAA["GABA-A receptor\nGABRA1 (P14867)\nAllosteric remodeling"]
        NMDAR["NMDA receptor\nGRIN2A (Q12879)\nNMDA current blockade"]
        MME["Enkephalinase / NEP\n(MME, P08473)\nInhibition by Semax, Selank"]
    end

    SX -->|"partial agonist"| MC4R
    SE -->|"allosteric modulation\ngene expression remodeling"| GABAA
    DS -->|"current potentiation"| GABAA
    DS -->|"NMDA blockade"| NMDAR
    SX --> MME
    SE --> MME
    DS -->|"Ca2+-dep release"| PENK["Met-enkephalin\n(PENK, P01210)"]
    MME -->|"inhibited: ENK preserved"| PENK
    PENK --> OPRM1["OPRM1/OPRD1\nGi/Go-coupled\nAnxiolytic, analgesic"]

    subgraph cAMP_arm["cAMP / PKA Cascade"]
        AC["Adenylyl cyclase\nADCY1/5/8"]
        PKA["PKA (PRKACA, P17612)"]
        CREB["CREB1 Ser133-P\n(P16220)"]
        GluA1["GluA1 Ser845-P\n(GRIA1, P42261)\nAMPA surface insertion"]
    end

    MC4R -->|"Galpha-s"| AC --> PKA
    PKA --> CREB
    PKA --> GluA1

    subgraph BDNF_arm["BDNF / TrkB Cascade"]
        BDNF["BDNF (P23560)\nTranscription via CRE promoter"]
        TrkB["TrkB (NTRK2, Q16620)\npTyr516 / pTyr817"]
        ERK["ERK1/2 (P27361/P28482)\nSHC-GRB2-SOS-Ras-Raf-MEK"]
        AKT["Akt (P31749)\nPI3K-PDK1-mTORC2"]
        CaMKII["CaMKII (Q9UQM7)\nGluA1 Ser831-P"]
        PLCg["PLCgamma1 (P19174)\nIP3 + DAG"]
    end

    CREB -->|"CRE-driven transcription"| BDNF
    SE -->|"BDNF mRNA upregulation"| BDNF
    DS -->|"HPA suppression\nindirect BDNF support"| BDNF
    BDNF --> TrkB
    TrkB --> ERK
    TrkB --> AKT
    TrkB --> PLCg
    PLCg -->|"IP3 → Ca2+"| CaMKII

    subgraph Outputs["Physiological Outputs"]
        LTP["LTP / Synaptic Plasticity\nCA1/CA3, Cortex"]
        MEM["Memory Consolidation\nHippocampal-dependent"]
        ANX["Anxiolysis\nAmygdala / PFC"]
        NURO["Neuroprotection\nAnti-apoptosis, Peri-infarct"]
        SLP["Sleep Architecture\nSlow-wave sleep"]
        HPA_out["HPA Normalization\nReduced cortisol"]
    end

    ERK --> LTP
    GluA1 --> LTP
    CaMKII --> LTP
    LTP --> MEM
    GABAA --> ANX
    OPRM1 --> ANX
    AKT --> NURO
    ERK --> NURO
    DS --> SLP
    DS --> HPA_out
    HPA_out --> BDNF

Physiological Outputs

Long-Term Potentiation and Memory Consolidation

The primary cognitive output of this pathway is enhanced hippocampal long-term potentiation (LTP). Three molecular events converge to lower the LTP induction threshold and increase its magnitude: (1) MC4R/PKA-mediated GluA1 Ser845 phosphorylation, which increases synaptic AMPA receptor density before any plasticity-inducing stimulus; (2) TrkB/CaMKII-mediated GluA1 Ser831 phosphorylation, which increases single-channel conductance after BDNF-TrkB engagement; and (3) ERK1/2-driven immediate-early gene transcription, which produces the structural synaptic changes required for late-phase LTP. These mechanisms operate across CA1, CA3, and cortical layers II/III.

In rodent behavioral models, Semax accelerates spatial learning acquisition in the Morris water maze, improves conditioned avoidance retention at 24-72 hours, and enhances novel object recognition discrimination at delays beyond 24 hours (PMID: 16996037). Selank activated learning in rats with initially poor learning ability after a single dose (Semenova et al., 2003) and restored memory and learning in alcohol-intoxicated rats with effects correlating with BDNF normalization (PMID: 31625062).

Anxiolysis and Stress Regulation

GABA-A allosteric remodeling by Selank produces anxiolytic effects comparable to medazepam (benzodiazepine) in head-to-head animal and clinical comparisons, without sedation, motor impairment, or amnestic effects (PMID: 18454096). The orexin/hypocretin suppression (HCRT mRNA -25-fold) likely contributes to reduced arousal-driven anxiety without the sedation of direct GABAergic agonism. Met-enkephalin preservation by both Semax and Selank reduces locus coeruleus and amygdalar firing through opioid Gi/Go-GIRK channel hyperpolarization.

DSIP suppresses ACTH and CRH-driven cortisol, which reduces hippocampal GR-mediated BDNF suppression and restores HPA diurnal rhythm. Chronic HPA normalization by DSIP is mechanistically complementary to the acute receptor-level anxiolysis of Selank: the former corrects the neuroendocrine context; the latter reduces anxiogenic signaling in the moment.

Neuroprotection

In permanent middle cerebral artery occlusion models, Semax reduced infarct volume by 25-40% and improved neurological deficit scores. The molecular basis includes: coordinate neurotrophin and Trk receptor upregulation in the peri-infarct penumbra (PMID: 19633950), ERK-mediated pro-survival gene transcription, PI3K/Akt-mediated BAD phosphorylation reducing apoptosis, and reduced neuroinflammatory transcripts (IL-1beta, TNF-alpha, IL-6) in the peri-infarct tissue.

DSIP pretreatment completely prevented hypoxia-induced mitochondrial respiratory chain impairment in rat brain (PMID: 7628639), providing a complementary metabolic mechanism for neuroprotection. Selank reduced IL-1beta, IL-6, TNF-alpha, and TGF-beta1 in social-stress models (Kolik and Nadorova), and its anti-inflammatory cytokine effects overlap with the neuro-immune interface relevant to neurodegenerative risk.

Sleep Architecture and Circadian Coupling

DSIP induces delta EEG activity (1-4 Hz slow-wave oscillations) following intraventricular or systemic administration in rodents. In clinical pilot observations, DSIP administration improved sleep quality, reduced sleep onset latency, increased slow-wave sleep duration, and improved daytime alertness and psychomotor performance in subjects with disturbed sleep (PMID: 6548970). Its modulation of pineal N-acetyltransferase activity links it to the melatonin synthesis rhythm independently of direct sleep induction, placing DSIP as a potential coupling signal between neuroendocrine state and circadian timing.

Related Compounds

Semax

Semax is an ACTH 4-10 analogue (Met-Glu-His-Phe-Pro-Gly-Pro) developed as a metabolically stable nootropic and neuroprotective peptide. Its primary mechanism flows through MC4R partial agonism, cAMP/PKA/CREB activation, and coordinate BDNF and TrkB upregulation in hippocampus and basal forebrain. Key mechanistic findings from primary literature:

• Single intranasal dose at 50 microg/kg increased rat hippocampal BDNF mRNA 3-fold, TrkB mRNA 2-fold, and phospho-TrkB 1.6-fold (PMID: 16996037).
• Radiolabeled Semax binds basal forebrain membranes with Kd of 2.4 nM, confirming specific high-affinity receptor engagement (PMID: 16635254).
• Coordinate upregulation of BDNF, NGF, NT-3, TrkA, TrkB, and TrkC in ischemic cortex within 3-72 hours of permanent MCAO (PMID: 19633950).
• Modulation of MAPK10/JNK3 and APP in intact hippocampus suggests calibration of stress-activated MAPK signaling threshold in the absence of pathology.
• Enkephalinase inhibition and dopaminergic system activation independently contribute to cognitive and anxiolytic effects (PMID: 16362768).

Full research context: Semax Research Hub.

Selank

Selank is a synthetic tuftsin analogue (Thr-Lys-Pro-Arg-Pro-Gly-Pro) registered in Russia for generalized anxiety disorder. It acts through four complementary mechanisms that converge on the same cognitive and anxiolytic outputs as Semax through distinct receptor entry points:

• GABA-A receptor allosteric remodeling: 45 of 84 surveyed GABA-related genes altered in rat frontal cortex at one hour; GABRE and GABRQ mRNA each -20-fold; GABRB3 +1.6-fold; GAD1 (GABA synthesis) upregulated (PMID: 26924987).
• DRD3 mRNA +3.4-fold in frontal cortex at one hour; DRD5 upregulated, implicating mesolimbic dopamine modulation (PMID: 26924987).
• Enkephalinase inhibition preserving endogenous Met- and Leu-enkephalin at the synapse.
• State-dependent BDNF normalization in hippocampus (Inozemtseva et al., 2008; PMID: 31625062).
• Head-to-head anxiolytic efficacy comparable to medazepam, without sedation or dependence, in a clinical trial of 62 participants including 30 with GAD using Hamilton Anxiety Rating Scale (PMID: 18454096).

Full research context: Selank Research Hub.

DSIP

DSIP (Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu) is a nonapeptide with circadian plasma rhythmicity whose encoding gene and dedicated receptor remain unidentified. It engages multiple neuromodulatory systems indirectly:

• GABA-A current potentiation and NMDA current blockade in hippocampal and cortical neurons.
• Calcium-dependent Met-enkephalin release from brainstem slices (PMID: 2706459), raising endogenous opioid tone without direct opioid receptor agonism.
• HPA axis suppression: reduced basal ACTH release, CRH blockade, and approximately 30% corticosterone reduction in rat models, with downstream relief of GR-mediated hippocampal BDNF suppression.
• Mitochondrial respiratory chain protection under hypoxia (PMID: 7628639).
• Slow-wave sleep induction and clinical improvement in disturbed sleep; improved daytime psychomotor performance in pilot observations (PMID: 6548970).

Full research context: DSIP Research Hub.

Pathway Interactions

The neuropeptide cognitive signaling pathway intersects with several networks documented elsewhere on this site:

• MAPK Cascade: ERK1/2 activation downstream of TrkB (via Ras/Raf/MEK) and MC4R (via EPAC/Rap1/B-Raf) is the central proliferative and plasticity-gene transcription arm. DSIP’s GILZ homology suggests additional modulation of the Raf-MEK junction. See MAPK Cascade.
• PI3K/Akt Pathway: TrkB-FRS2-PI3K-Akt is the neuronal survival arm, phosphorylating BAD and activating mTORC1 for dendritic protein synthesis. See PI3K/Akt Pathway.
• Melanocortin Axis: MC4R is the primary receptor for Semax in the hippocampus. The broader POMC processing network and MC receptor family context is covered at Melanocortin Axis.
• Thymic Immunomodulation: Selank’s anti-inflammatory cytokine modulation (IL-1beta, IL-6, TNF-alpha, TGF-beta1) and NK cell enhancement overlap with the neuro-immune interface. See Thymic Immunomodulation.

Key References

• Monnier M, Dudler L, Gachter R, Schoenenberger GA. Delta sleep-inducing peptide (DSIP): EEG and motor activity in rabbits following intravenous administration. Neurosci Lett. 1977;6(1):9-13. PMID: 568769
• Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analogue of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54-60. PMID: 16996037
• Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax administrated intranasally binds basal forebrain neurons and increases BDNF protein content. J Neurochem. 2006;97 Suppl 1:82-86. PMID: 16635254
• Agapova TY, Agniullin YV, Silachev DN, et al. Effects of Semax and Pro-Gly-Pro on the expression of BDNF and its receptor TrkB after cerebral ischemia-reperfusion. Cell Mol Neurobiol. 2009;30(1):67-78. PMID: 19633950
• Shen Y, Fu WY, Cheng EY, et al. Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism. J Neurosci. 2013;33(2):464-472. PMID: 23303927
• Volkova A, Shadrina M, Kolomin T, et al. Selank administration affects the expression of some genes involved in GABAergic neurotransmission. Front Pharmacol. 2016;7:31. PMID: 26924987
• Zozulia AA, Neznamov GG, Syunyakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic Selank in the treatment of generalized anxiety disorders and neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38-48. PMID: 18454096
• Kolik LG, Nadorova AV, Konstantinopolsky MA. Efficacy of peptide anxiolytic Selank and afobazole in modelling anxiety and cognitive disorders in behavior in animals with excessive ethanol consumption. Bull Exp Biol Med. 2019;167(4):490-494. PMID: 31625062
• Iyer V, McCann SM. Delta sleep inducing peptide (DSIP) stimulates the release of immunoreactive somatostatin (SRIF) from rat hypothalamus in vitro. Peptides. 1989;10(3):547-553. PMID: 2706459
• Khvatova EM, Samartzev VN, Zagoskin PP, et al. Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress influence on this process. Peptides. 1995;16(6):1133-1138. PMID: 7628639
• Schneider-Helmert D. DSIP in insomnia. Eur Neurol. 1984;23(5):358-363. PMID: 6548970
• Levitskaya NG, Sebentsova EA, Glazova NY, et al. 4-10 Fragment of ACTH suppresses the development of submorphine dependence in rats. Eur Neuropsychopharmacol. 2006;16(2):112-118. PMID: 16362768

See also

Compounds that engage this pathway:

• Semax
• Selank
• Dsip