RPEP-00045 · 1987A single injection of kainic acid (1 microgram) into rat brains caused seizures lasting 3 to 6 hours. During seizures, hippocampal met-enkephalin dropped 31% and dynorphin A dropped 63%, suggesting these opioid peptides were being released.
By 24 hours, levels returned to normal. By 48 hours, met-enkephalin surged to 270% of normal and dynorphin to 150%. The brain had ramped up production to replace what was used.
The biosynthetic machinery confirmed this: mRNA for preproenkephalin (the genetic template for making enkephalin) jumped to 400% of control at 6 hours. The actual precursor protein followed at 24 hours, reaching 300% of control.
The seizure-induced shaking behavior (wet-dog shakes) was directly linked to enkephalin. Naloxone (an opioid blocker) reduced the shaking. Anti-enkephalin antibodies also reduced it. Injecting enkephalin peptides into the hippocampus mimicked the shaking.
Hong, J S; Grimes, L; Kanamatsu, T; McGinty, J F · Animal Study
RPEP-00051 · 1987Severe brain injury (3.0 to 4.0 atmospheres of pressure) caused dynorphin to increase significantly in five brain regions: striatum, frontal cortex, parietal cortex, pons, and medulla. These were the same regions with the worst tissue damage.
Beta-endorphin decreased in the hypothalamus after severe injury but increased in the anterior pituitary after both mild and severe trauma. Enkephalin levels did not change at any injury level.
The dynorphin increase in the medulla was significantly correlated with falling mean arterial blood pressure after severe injury. This suggests dynorphin release may contribute to the cardiovascular collapse that worsens outcomes after head trauma.
McIntosh, T K; Head, V A; Faden, A I · Animal Study
RPEP-00052 · 1987Dynorphin A accumulated in injured brain regions after fluid-percussion brain injury in cats. These same regions showed significant decreases in cerebral blood flow. Enkephalin did not accumulate.
The opioid antagonist Win-(-), given 15 minutes after injury, significantly improved multiple outcomes: mean arterial blood pressure increased, EEG amplitude (brain wave activity) improved, regional cerebral blood flow recovered, and both the severity and incidence of brain hemorrhage decreased. Survival after injury was significantly better.
The control was elegant: Win-(+), the mirror-image version of the same drug that cannot bind opioid receptors, had no effect. Neither did saline. This confirmed the benefits came specifically from blocking opioid receptors.
McIntosh, T K; Hayes, R L; DeWitt, D S; Agura, V; Faden, A I · Animal Study
RPEP-00064 · 1988After middle cerebral artery occlusion (a stroke model) in rats, the opioid antagonist WIN at doses of 0.4 to 400 micrograms/kg produced several benefits.
All WIN doses significantly increased mean arterial blood pressure compared to saline controls. At the optimal dose of 40 micrograms/kg, rats showed significantly greater EEG (brain wave) recovery and higher neurological scores at 24 hours compared to controls.
Neurological outcome correlated with brain wave recovery on the injured side, confirming the measures tracked together.
However, 24-hour mortality and infarct (dead tissue) size were not significantly different from controls. The drug improved functional recovery without reducing the actual area of brain death.
At 1 hour after stroke, there were no significant changes in dynorphin, enkephalin, or endorphin levels in the injured vs. uninjured brain hemisphere. This was unexpected given the changes seen in trauma models.
Andrews, B T; McIntosh, T K; Gonzales, M F; Weinstein, P R; Faden, A I · Animal Study
RPEP-00076 · 1988After seizures (from electroshock, kainic acid, or kindling), both dynorphin and enkephalin initially decrease in the hippocampus, indicating release. But their recovery patterns differ dramatically.
Enkephalin shows a rapid, sustained rebound above normal levels after all three seizure types. Dynorphin shows a large, sustained decrease after electroshock and kindling, with slow recovery.
Mu-opioid receptor antagonists shortened the kindling process (where repeated mild stimulation eventually produces seizures). This strongly suggests brain opioid peptides are involved in how seizure susceptibility develops.
Enkephalin in the hippocampus appears to mediate wet-dog shakes (a specific seizure behavior seen in rodents), connecting it to the opioid withdrawal syndrome.
Hong, J S; McGinty, J F; Grimes, L; Kanamatsu, T; Obie, J; Mitchell, C L · Review
RPEP-00088 · 1988Regardless of which nerve was cut (right or left sciatic, both sciatic, right brachial plexus, saphenous, or sural), the same brain-wide pattern emerged.
Beta-endorphin decreased significantly in all brain areas except the striatum. Met-enkephalin increased in all brain areas and in the affected spinal cord segments. Substance P, somatostatin, and dynorphin were unaffected.
The changes appeared within 24 hours of surgery and persisted for at least 4 months, indicating a long-lasting reorganization of the opioid system.
There was no lateralization: unilateral nerve cuts produced bilateral brain changes. This means local nerve damage triggers a global brain response.
Serotonergic drugs normalized beta-endorphin levels, suggesting the serotonin system mediates the opioid changes after nerve injury.
Panerai, A E; Sacerdote, P; Brini, A; Bianchi, M; Mantegazza, P · Animal Study
RPEP-00096 · 1988CSF from rats that had just experienced an electroshock seizure significantly raised seizure thresholds in recipient rats when injected into their brain ventricles.
This anticonvulsant activity was blocked by high-dose naloxone and by the selective delta-opioid antagonist ICI 174,864. This identified delta-opioid receptors as the mediators.
The active substance was destroyed by heat (90°C) and by trypsin (a protein-digesting enzyme), confirming it is a peptide. It passed through 10,000 dalton membranes but not 5,000 dalton membranes, putting its size between 5,000-10,000 daltons.
Post-seizure CSF had increased beta-endorphin (31 amino acids, ~3,500 daltons) but not dynorphin A, leu-enkephalin, or met-enkephalin. However, hidden met-enkephalin sequences (released by trypsin digestion of larger peptides) were found.
The size (5,000-10,000 Da) and delta-receptor specificity do not match any known opioid peptide, suggesting an undiscovered anticonvulsant opioid peptide.
Tortella, F C; Long, J B · Animal Study
RPEP-00184 · 1991Cerebrospinal fluid MERGL levels were significantly low in Parkinson's patients after overnight medication withdrawal. Steady-state levodopa infusion did not restore them.
Baronti, F; Conant, K E; Giuffra, M; Davis, T L; Brughitta, G; Iadarola, M J; Berrettini, W H; Chase, T N; Mouradian, M M · Cross Sectional
RPEP-00190 · 1991Kainic acid seizures increased hippocampal prodynorphin and proenkephalin mRNA while decreasing dynorphin A and met-enkephalin peptide levels, both proportional to seizure severity.
Douglass, J; Grimes, L; Shook, J; Lee, P H; Hong, J S · Animal Study
RPEP-00206 · 1991Met-enkephalin was significantly elevated in cortex, hippocampus, and brainstem of tg/tg epileptic mice. Beta-endorphin and dynorphin were unchanged.
Patel, V K; Abbott, L C; Rattan, A K; Tejwani, G A · Animal Study
RPEP-00231 · 1992Kappa agonists U-62,066E and ethylketocyclazocine inhibited potassium-evoked glutamate and dynorphin B release from mossy fiber synaptosomes. Mu (DAGO) and delta (DPDPE) agonists were inactive.
Gannon, R L; Terrian, D M · In Vitro
RPEP-00237 · 1992Both seizure types caused initial opioid release. Long-term: enkephalin biosynthesis increased, dynorphin biosynthesis drastically decreased. These peptides are in distinct hippocampal pathways.
Hong, J S · Animal Study
RPEP-00258 · 1993Plasma and CSF levels of all three opioid peptides were elevated in asphyxiated newborns vs. controls, with highest levels in those with cerebral injury.
Cao, L; Qian, P D; Jing, L J; Liang, Q J; Zhao, Z Z · Cross Sectional
RPEP-00293 · 1994Alpha-neo-endorphin was the dominant prodynorphin peptide in primate brain, with striatal concentrations significantly exceeding cortical levels across all four peptides.
Healy, D J; Meador-Woodruff, J H · Animal Study
RPEP-00300 · 1994The N-terminal to C-terminal beta-endorphin ratio was significantly different in children with autism compared to healthy controls and children with Rett syndrome.
Leboyer, M; Bouvard, M P; Recasens, C; Philippe, A; Guilloud-Bataille, M; Bondoux, D; Tabuteau, F; Dugas, M; Panksepp, J; Launay, J M · Cross Sectional
RPEP-00302 · 1994Opioid peptides including dynorphins produced voltage-dependent changes in potassium currents in CA3 neurons, resolving contradictory findings from prior studies.
Moore, S D; Madamba, S G; Schweitzer, P; Siggins, G R · In Vitro
RPEP-00310 · 1994Naloxone restored urinary function in chronic spinal cats but not acute ones, demonstrating opioid system plasticity that contributes to urinary retention after spinal cord injury.
Thor, K B; Roppolo, J R; Kawatani, M; Erdman, S; deGroat, W C · Animal Study
RPEP-00311 · 1994Both met-enkephalin and leu-enkephalin are present in separate neuron populations in the dogfish shark brain, but dynorphin-related peptides were not detected.
Vallarino, M; Bucharles, C; Facchinetti, F; Vaudry, H · Animal Study
RPEP-00332 · 1995Hippocampal dynorphins and enkephalins regulate synaptic transmission efficiency at granule cell synapses, with opioid levels changing dramatically under different physiological and pathological conditions.
Morris, B J; Johnston, H M · Review
RPEP-00349 · 1995Fulminant hepatic failure significantly altered Met-enkephalin, Leu-enkephalin, dynorphin A, and beta-endorphin levels in multiple brain regions and plasma.
Yurdaydin, C; Li, Y; Ha, J H; Jones, E A; Rothman, R; Basile, A S · Animal Study
RPEP-00355 · 1996Endogenous opioid peptides in cerebral perivascular nerves and CSF actively regulate cerebral blood flow through opiate receptors, with concentrations changing in response to perfusion pressure and oxygen tension.
Benyó, Z; Wahl, M · Review
RPEP-00385 · 1996Proenkephalin-derived peptides increase hippocampal excitability via mu/delta receptors, while prodynorphin-derived peptides decrease it via kappa receptors, providing opposing regulation of memory circuits.
Simmons, M L; Chavkin, C · Review
RPEP-00446 · 1998Fluid percussion brain injury in newborn pigs impaired opioid-mediated cerebral artery dilation by disrupting prostaglandin release pathways, blunting the normal vasodilatory response.
Al-Turki, A; Armstead, W M · Animal Study
RPEP-00465 · 1998BPC-157 blocked acute amphetamine-induced stereotypy and prevented haloperidol-induced dopamine supersensitivity to amphetamine, without affecting normal baseline behavior.
Jelovac, N; Sikirić, P; Rucman, R; Petek, M; Perović, D; Konjevoda, P; Marović, A; Seiwerth, S; Grabarević, Z; Sumajstorcić, J; Dodig, G; Perić, J · Animal Study
RPEP-00489 · 1998Beta-casomorphin-5 stimulated neurite outgrowth in Neuro-2a cells at picomolar concentrations via mu-opioid receptors, demonstrated by naloxone reversibility and DAMGO replication of the effect.
Sakaguchi, M; Murayama, K; Yabe, K; Satoh, M; Takeuchi, M; Matsumura, E · In Vitro
RPEP-00528 · 1999BPC-157 attenuated catalepsy and gastric ulcers induced by haloperidol, fluphenazine, and reserpine at both 10 μg/kg and 10 ng/kg doses, demonstrating broad protective effects against neuroleptic side effects.
Jelovac, N; Sikiric, P; Rucman, R; Petek, M; Marovic, A; Perovic, D; Seiwerth, S; Mise, S; Turkovic, B; Dodig, G; Miklic, P; Buljat, G; Prkacin, I · Animal Study
RPEP-00558 · 1999BPC-157 attenuated both MPTP- and haloperidol-induced Parkinson's-like symptoms in mice while simultaneously protecting against gastric lesions caused by these parkinsongenic agents.
Sikiric, P; Marovic, A; Matoz, W; Anic, T; Buljat, G; Mikus, D; Stancic-Rokotov, D; Separovic, J; Seiwerth, S; Grabarevic, Z; Rucman, R; Petek, M; Ziger, T; Sebecic, B; Zoricic, I; Turkovic, B; Aralica, G; Perovic, D; Duplancic, B; Lovric-Bencic, M; Rotkvic, I; Mise, S; Jagic, V; Hahn, V · Animal Study
RPEP-00568 · 1999Endogenous thymosin alpha-1 protein and mRNA were detected in rat CNS neurons, astrocytes, and oligodendrocytes, establishing it as a brain-derived peptide that may contribute to neurotrophic signaling.
Turrini, P; Aloe, L · Animal Study
RPEP-00593 · 2000Self-assembling peptide scaffolds supported extensive neurite outgrowth and formation of active, functional synapses, demonstrating programmable peptide-based materials for neural regeneration.
Holmes, T C; de Lacalle, S; Su, X; Liu, G; Rich, A; Zhang, S · In Vitro
RPEP-00620 · 2000Complete dopamine system failure (combined haloperidol + reserpine) produced severe gastric lesions. BPC-157 provided superior healing compared to ranitidine, atropine, and other agents while also reducing associated catalepsy.
Sikiric, P; Separovic, J; Buljat, G; Anic, T; Stancic-Rokotov, D; Mikus, D; Duplancic, B; Marovic, A; Zoricic, I; Prkacin, I; Lovric-Bencic, M; Aralica, G; Ziger, T; Perovic, D; Jelovac, N; Dodig, G; Rotkvic, I; Mise, S; Seiwerth, S; Turkovic, B; Grabarevic, Z; Petek, M; Rucman, R · Animal Study
RPEP-00651 · 2001BPC-157, omeprazole, and bromocriptine healed haloperidol-induced gastric lesions, while atropine, lansoprazole, and cimetidine failed, demonstrating the lesions are dopamine-mediated and BPC-157 acts through dopaminergic mechanisms.
Bilic, I; Zoricic, I; Anic, T; Separovic, J; Stancic-Rokotov, D; Mikus, D; Buljat, G; Ivankovic, D; Aralica, G; Prkacin, I; Perovic, D; Mise, S; Rotkvic, I; Petek, M; Rucman, R; Seiwerth, S; Sikiric, P · Animal Study
RPEP-00771 · 2002BPC-157 attenuated chronic amphetamine-induced tolerance, behavioral sensitization, and withdrawal disturbances in rats, demonstrating comprehensive dopamine system stabilization against stimulant drug-induced neuroplasticity.
Sikiric, Predrag; Jelovac, Nikola; Jelovac-Gjeldum, Andjelka; Dodig, Goran; Staresinic, Mario; Anic, Tomislav; Zoricic, Ivan; Rak, Davor; Perovic, Darko; Aralica, Gorana; Buljat, Gojko; Prkacin, Ingrid; Lovric-Bencic, Martina; Separovic, Jadranka; Seiwerth, Sven; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Ziger, Tihomil; Boban-Blagaic, Alenka; Bedekovic, Vlado; Tonkic, Ante; Babic, Slaven · Animal Study
RPEP-00778 · 2002Intrathecal big dynorphin at femtomole doses caused nociceptive behavior through NMDA receptor activation (blocked by MK-801) but not through opioid receptors (not blocked by naloxone), with higher doses causing reversible paralysis.
Tan-No, Koichi; Esashi, Akihisa; Nakagawasai, Osamu; Niijima, Fukie; Tadano, Takeshi; Sakurada, Chikai; Sakurada, Tsukasa; Bakalkin, Georgy; Terenius, Lars; Kisara, Kensuke · Animal Study
RPEP-00886 · 2004BPC-157 protected against acute ethanol toxicity (reduced mortality, behavioral impairment, gastric damage) and chronic alcohol effects (reduced intake, liver protection), demonstrating comprehensive anti-alcohol therapeutic potential.
Blagaic, Alenka Boban; Blagaic, Vladimir; Romic, Zeljko; Sikiric, Predrag · Animal Study
RPEP-00987 · 2004BPC-157 produced region-specific changes in brain serotonin synthesis measured by alpha-methyl-L-tryptophan autoradiography — increasing synthesis in some regions while decreasing it in others, providing the serotonergic basis for its mood-modulating properties.
Tohyama, Y; Sikirić, P; Diksic, M · Animal Study
RPEP-00994 · 2004Endogenous opioid peptides have extensive non-opioid receptor activities: immune modulation, cell proliferation control (via OGFr), cardiovascular protection, neuroprotection, and antimicrobial effects — mediated through non-classical receptors and direct physicochemical mechanisms.
Wollemann, Mária; Benyhe, Sándor · Review
RPEP-01012 · 2005BPC-157 effectively counteracted serotonin syndrome signs (hyperthermia, tremor, rigidity, agitation) induced by multiple serotonergic drugs in rats, demonstrating serotonergic system modulation complementing its known dopaminergic and GABAergic interactions.
Boban Blagaic, Alenka; Blagaic, Vladimir; Mirt, Mirela; Jelovac, Nikola; Dodig, Goran; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Anic, Tomislav; Dubovecak, Miroslav; Staresinic, Mario; Seiwerth, Sven; Sikiric, Predrag · Animal Study
RPEP-01018 · 2005Hexarelin reduced neonatal brain injury in a hypoxia-ischemia model and altered Akt/GSK-3β phosphorylation — activating pro-survival signaling cascades for direct GH-independent neuroprotection in the developing brain.
Brywe, Katarina G; Leverin, Anna-Lena; Gustavsson, Malin; Mallard, Carina; Granata, Riccarda; Destefanis, Silvia; Volante, Marco; Hagberg, Henrik; Ghigo, Ezio; Isgaard, Jörgen · Animal Study
RPEP-01055 · 2005Intranasal oxytocin attenuated amygdala reactivity to threatening facial expressions measured by fMRI in healthy humans, providing the first neural imaging evidence for oxytocin's anxiolytic mechanism through direct fear-circuit modulation.
Kirsch, Peter; Esslinger, Christine; Chen, Qiang; Mier, Daniela; Lis, Stefanie; Siddhanti, Sarina; Gruppe, Harald; Mattay, Venkata S; Gallhofer, Bernd; Meyer-Lindenberg, Andreas · RCT
RPEP-01108 · 2005SS-31, a cell-permeable peptide targeting the inner mitochondrial membrane, prevented mitochondrial depolarization and apoptosis in neuronal cells exposed to oxidative stress — demonstrating precision subcellular peptide targeting for protecting the cell's energy source.
Zhao, Kesheng; Luo, Guoxiong; Giannelli, Serena; Szeto, Hazel H · In Vitro
RPEP-01127 · 2006GHRP-6 protected neurons from glutamate-induced excitotoxic death through survival signaling pathway activation, demonstrating direct GH-independent neuroprotection against the primary mechanism of stroke and neurodegenerative brain cell death.
Delgado-Rubín de Célix, Arancha; Chowen, Julie A; Argente, Jesús; Frago, Laura M · Animal Study
RPEP-01129 · 2006Semax upregulated BDNF mRNA and TrkB receptor expression in the rat hippocampus, providing the neurotrophic molecular mechanism for its documented cognitive enhancement and neuroprotective effects — BDNF is the brain's primary growth and survival factor.
Dolotov, Oleg V; Karpenko, Ekaterina A; Inozemtseva, Lyudmila S; Seredenina, Tamara S; Levitskaya, Natalia G; Rozyczka, Joanna; Dubynina, Elena V; Novosadova, Ekaterina V; Andreeva, Lyudmila A; Alfeeva, Lyudmila Yu; Kamensky, Andrey A; Grivennikov, Igor A; Myasoedov, Nikolay F; Engele, Jürgen · Animal Study
RPEP-01130 · 2006Semax (ACTH 4-10 analog) showed specific binding to rat brain tissue and increased brain-derived neurotrophic factor (BDNF) protein levels, confirming receptor-mediated neurotrophin enhancement as the mechanism for its nootropic and neuroprotective activities.
Dolotov, Oleg V; Karpenko, Ekaterina A; Seredenina, Tamara S; Inozemtseva, Lyudmila S; Levitskaya, Natalia G; Zolotarev, Yuriy A; Kamensky, Andrey A; Grivennikov, Igor A; Engele, Juergen; Myasoedov, Nikolay F · Animal Study
RPEP-01216 · 2007Mitochondria-targeted peptides (SS-31 and analogs) reduced myocardial infarct size by up to 60% in rat ischemia-reperfusion, with efficacy when given before ischemia or at reperfusion — demonstrating potent cardioprotection through preservation of mitochondrial function.
Cho, Janghyun; Won, Kyungheon; Wu, DunLi; Soong, Yi; Liu, Shaoyi; Szeto, Hazel H; Hong, Mun K · Animal Study
RPEP-01277 · 2007Noopept (proline-containing dipeptide) restored spatial memory in brain-lesioned rats and increased hippocampal BDNF immunoreactivity, establishing BDNF upregulation as the neurotrophic mechanism for Noopept's cognitive-enhancing and neuroprotective activities.
Ostrovskaya, Rita U; Gruden, Marina A; Bobkova, Natalya A; Sewell, Robert D E; Gudasheva, Tatyana A; Samokhin, Alexander N; Seredinin, Sergey B; Noppe, Wim; Sherstnev, Vladimir V; Morozova-Roche, Ludmilla A · Animal Study
RPEP-01295 · 2007SS-31 (mitochondria-targeted peptide) prevented mitochondrial depolarization and apoptosis in pancreatic islet cells, preserved glucose-stimulated insulin secretion, and improved glycemic control in diabetic animals — protecting the beta-cells that diabetes progressively destroys.
Thomas, Dolca A; Stauffer, Craig; Zhao, Kesheng; Yang, Hua; Sharma, Vijay K; Szeto, Hazel H; Suthanthiran, Manikkam · Animal Study
RPEP-01312 · 2008Intranasal oxytocin in healthy men increased trust behavior AND prevented trust adaptation (trust reduction) after betrayal in a social investment game, shaping the neural circuitry of both trust formation and trust resilience — with implications for social anxiety and autism.
Baumgartner, Thomas; Heinrichs, Markus; Vonlanthen, Aline; Fischbacher, Urs; Fehr, Ernst · RCT
RPEP-01349 · 2008GH/IGF-1 axis decline correlates with Alzheimer's disease progression, with IGF-1 supporting neuronal survival, beta-amyloid clearance, and synaptic function — GH secretagogues that restore this axis may offer neuroprotective therapeutic benefit for dementia.
Gómez, José Manuel · Review
RPEP-01387 · 2008Cell-permeable antioxidant peptide (SS-31 family) reduced renal tubular apoptosis, oxidative damage, and fibrosis in unilateral ureteral obstruction rats — expanding mitochondria-targeted peptide therapy to kidney protection for obstructive and other renal diseases.
Mizuguchi, Yasunori; Chen, Jie; Seshan, Surya V; Poppas, Dix P; Szeto, Hazel H; Felsen, Diane · Animal Study
RPEP-01418 · 2008MK-677 successfully increased GH/IGF-1 in AD patients but showed no clinical benefit on cognitive decline, ADAS-cog, or CDR-sb over the trial period — proving GH axis restoration alone is insufficient for treating established Alzheimer's disease.
Sevigny, J J; Ryan, J M; van Dyck, C H; Peng, Y; Lines, C R; Nessly, M L · RCT