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peptide science.

Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses.

Endocrinology

John-Paul Baird, Angela Choe, Jasmine L Loveland +4 more

Orexin-A (ORXA) is an orexigenic neuropeptide produced by the lateral hypothalamus that increases food intake when injected into the brain ventricles or forebrain nuclei. We used a licking microstructure analysis to evaluate hindbrain and forebrain ORXA effects in intact and hindbrain-lesioned rats, to identify the motivational and anatomical bases of ORXA hyperphagia. Intact rats with cannulas in the fourth brain ventricle (4V) received vehicle (artificial cerebrospinal fluid) or ORXA (0.1, 0.4, 1, or 10 nm) injections before 90 min access to 0.1 m sucrose. Meal size and frequency were increased in a double-dissociated manner by the 1 and 10 nm doses, respectively. In experiment 2, 4V 1 nm ORXA was applied to rats offered solutions varied in caloric and gustatory intensity (water and 0.1 and 1 m sucrose). ORXA increased meal frequency for all tastants. ORXA increased meal size only for 0.1 m sucrose, by prolonging the meal without affecting early ingestion rate or lick burst size, suggesting that 4V ORXA influenced inhibitory postingestive feedback rather than taste evaluation. In experiment 3, rats with cannulas in the third ventricle (3V) received dorsal medullary lesions centered on the area postrema (APX group) or sham procedures, and licking for water and 0.1 and 1 m sucrose was evaluated after 1 nm 3V ORXA/artificial cerebrospinal fluid injections. The 3V ORXA increased 0.1 m sucrose meal size and meal frequency for all tastants in the sham group, as observed after 4V ORXA in experiment 2. In the APX group, 3V ORXA injections influenced meal frequency, but they no longer increased meal size. However, the APX rats increased meal size for 0.1 m sucrose after food and water deprivation and after 3V angiotensin II injection. They also showed meal size suppression after 3V injection of the melanocortin-3/4 receptor agonist melanotan II (1 nm). These findings suggest that the area postrema and subjacent nucleus of the solitary tract are necessary for increases in consummatory (meal size) but not appetitive (meal frequency) responses to 3V ORXA. The meal size increases may be due to reduced postingestive feedback inhibition induced by ORXA delivered to either the hindbrain or forebrain ventricles.

In vitro and in vivo effects of mercuric chloride on thymic endocrine activity, NK and NKT cell cytotoxicity, cytokine profiles (IL-2, IFN-gamma, IL-6): role of the nitric oxide-L-arginine pathway.

Int Immunopharmacol

Lory Santarelli, Massimo Bracci, Eugenio Mocchegiani

Mercury (Hg2+) affects cell-mediated immunity, including thymulin production. Thymulin, a zinc-dependent thymic hormone synthesized by thymic epithelial cells (TECs), is involved in NK cell cytotoxicity and Th1 cytokine production (IL-2 and IFN-gamma), which in turn affect both NKT and classic NK spleen cell cytotoxicity. High doses of Hg2+ induce an inflammatory status, increased production of IL-6 and consequent Th1/Th2 imbalance as well as cell-mediated immune depression. The mechanisms by which Hg+ affects the cell-mediated immune response are still unclear. The nitric oxide (NO) pathway may be implicated. The aim of this work was to further explore its noxious role in innate and adaptive immunity and to study the possible role played by the NO pathway. Young Balb/c mice treated in vivo for 1 month with 1.0 mg HgCl2/kg b.w. showed low thymulin activity, depressed NO production (as measured by nitrite and nitrate plasma levels), impaired classic NK spleen cell cytotoxicity, decreased Th1 (IL-2 and IFN-gamma) cytokine profiles, and increased IL-6 production. In vitro, 10(-6) M of HgCl2 inhibited active thymulin kinetics, TEC proliferation, NKT cell cytotoxicity and Th1 cytokine production, whereas IL-6 increased. L-arginine restored thymulin activity, TEC proliferation, NKT cytotoxicity, cytokine profiles and nitrite and nitrate plasma levels both in vivo and in vitro. Since L-arginine is the substrate for NO production, it may compensate for the cell-mediated immune defect induced by HgCl2, via the arginine-NO-pathway. L-arginine is also able to reduce glomerular kidney IgG antibodies deposits induced by higher dose of HgCl2 administration.

[Clinical and electroencephalographic characteristic of noopept in patients with mild cognitive impairment of posttraumatic and vascular origin].

Zh Nevrol Psikhiatr Im S S Korsakova

V K Bochkarev, E S Teleshova, S A Siuniakov +2 more

An effect of a new nootropic drug noopept on the dynamics of main EEG rhythms and narrow-band spectral EEG characteristics in patients with cerebral asthenic and cognitive disturbances caused by traumas or vascular brain diseases has been studied. Noopept caused the EEG changes characteristic of the action of nootropics: the increase of alpha- and beta-rhythms power and reduction of delta-rhythms power. The reaction of alpha-rhythm was provided mostly by the dynamics of its low and medium frequencies (6,7-10,2 Hz), the changes of beta-rhythm were augmented in frontal and attenuated in occipital areas. The analysis of frequency and spatial structure of EEG changes reveals that noopept exerts a nonspecific activation and anxyolytic effect. The differences in EEG changes depending on the brain pathology were found. The EEG indices of nootropic effect of the drug were most obvious in cerebral vascular diseases. The EEG changes in posttraumatic brain lesion were less typical.

Genotype-dependent characteristics of behavior in mice in cognitive tests. The effects of Noopept.

Neurosci Behav Physiol

A P Bel'nik, R U Ostrovskaya, I I Poletaeva

Male C57BL/6J, BALB/c, and DBA/2J mice showed differences in their abilities to perform two cognitive tests. C57BL/6J mice had good learning ability and memory trace retention (at 10 days) in a simplified Morris maze, while BALB/c mice had low levels of memory trace retention and DBA/2J mice had low learning ability in this test. I.p. administration of the nootropic agent Noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) at a dose of 0.5 mg/kg 15 min before the start of the test induced significant improvements in long-term memory in this test in BALB/c mice but no further improvement in C57BL/6J mice, and had no effect in DBA/2J mice. On testing the ability to extrapolate the direction of movement of a stimulus, administration of Noopept increased the proportion of correct responses in C57BL/6J and BALB/c mice, but had no effect in DBA/2J mice.

Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats).

Bull Exp Biol Med

R U Ostrovskaya, A P Belnik, Z I Storozheva

Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to beta-amyloid25-35. Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases).

Co-expression of IGF-1 family members with myogenic regulatory factors following acute damaging muscle-lengthening contractions in humans.

J Physiol

Bryon R McKay, Ciara E O'Reilly, Stuart M Phillips +2 more

Muscle regeneration following injury is dependent on the ability of muscle satellite cells to activate, proliferate and fuse with damaged fibres. This process is controlled by the myogenic regulatory factors (MRF). Little is known about the temporal relation of the MRF with the expression of known myogenic growth factors (i.e. IGF-1) in humans following muscle damage. Eight subjects (20.6 +/- 2.1 years; 81.4 +/- 9.8 kg) performed 300 lengthening contractions (180 deg s(-1)) of their knee extensors in one leg on a dynamometer. Blood and muscle samples were collected before and at 4 (T4), 24 (T24), 72 (T72) and 120 h (T120) post-exercise. Mechano growth factor (MGF), IGF-1Ea and IGF-1Eb mRNA were quantified. Serum IGF-1 did not change over the post-exercise time course. IGF-1Ea and IGF-1Eb mRNA increased approximately 4- to 6-fold by T72 (P < 0.01) and MGF mRNA expression peaked at T24 (P = 0.005). MyoD mRNA expression increased approximately 2-fold at T4 (P < 0.05). Myf5 expression peaked at T24 (P < 0.05), while MRF4 and myogenin mRNA expression peaked at T72 (P < 0.05). Myf5 expression strongly correlated with the increase in MGF mRNA (r(2) = 0.83; P = 0.03), while MRF4 was correlated with both IGF-1Ea and -Eb (r(2) = 0.90; r(2) = 0.81, respectively; P < 0.05). Immunofluorescence analysis showed IGF-1 protein expression localized to satellite cells at T24, and to satellite cells and the myofibre at T72 and T120; IGF-1 was not detected at T0 or T4. These results suggest that the temporal response of MGF is probably related to the activation/proliferation phase of the myogenic programme as marked by an increase in both Myf5 and MyoD, while IGF-1Ea and -Eb may be temporally related to differentiation as marked by an increase in MRF4 and myogenin expression following acute muscle damage.

[Effects of heptapeptide selank on the content of monoamines and their metabolites in the brain of BALB/C and C57Bl/6 mice: a comparative study].

Eksp Klin Farmakol

V B Narkevich, V S Kudrin, P M Klodt +4 more

The effect of heptapeptide selank on the content of neurotransmitter monoamines and its metabolites in the brain structures of BALB/C and C57Bl/6 line mice under conditions of the open-field test were studied. Significant interstrain differences in the content of norepinephrine (NE), dopamine (DA), serotonin (5-HT) as well as in the levels of their metabolites in hippocampus, hypothalamus, striatum and frontal cortex of C57Bl/6 and BALB/C mice were demonstrated. In particular, the content of 5-HT and its metabolite 5-oxyindolacetic acid (5-HIAA) in hippocampus of BALB/C mice (with passive stress response) was higher than in the same structure of C57Bl/6 (stress-susceptible) animals. The injection of selank (0.3 mg/kg) led to an increase in the NE level in the hypothalamus of both mice strains. At the same time, selank produced opposite effects on the content of DA metabolites: the concentrations of dioxyphenylacetic (DOPAC) and homovanillic (HVA) acids were found to increase in frontal cortex and hippocampus of C57Bl/6 mice, while the same parameters in BALB/C mice were demonstrated to decrease. Selank induced a decrease in 5-HT and 5-HIAA levels in the hippocampus of BALB/C mice, but did not affect these parameters in C57Bl/6 animals. The obtained results are indicative of selectivity of the anxiolytic effects of selank.

Perinatal undernutrition modifies cell proliferation and brain-derived neurotrophic factor levels during critical time-windows for hypothalamic and hippocampal development in the male rat.

J Neuroendocrinol

B Coupé, I Dutriez-Casteloot, C Breton +7 more

Maternal perinatal undernutrition (MPU) modifies the activity of the hypothalamic-pituitary-adrenal axis and sensitises to the development of metabolic and cognitive adult diseases. Because the hypothalamus and hippocampus are involved in the regulation of neuroendocrine activity, energy metabolism and cognition, we hypothesised that a maternal 50% food restriction (FR50) from day 14 of pregnancy (E14) until postnatal day 21 (P21) would affect the development of these structures in male rat offspring. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) and cell proliferation [analysed by 5-bromodeoxyuridine (BrdU) incorporation] were compared in both control and FR50 rats from E21 to P22. Although the pattern of the evolution of BDNF concentration and cell proliferation throughout development was not strikingly different between groups, several disturbances at specific developmental stages were observed. FR50 rats exhibited a delayed increase of hippocampal BDNF content whereas, in the hypothalamus, BDNF level was augmented from E21 to P14 and associated, at this latter stage, with an increased mRNA expression of TRkB-T2. In both groups, a correlation between BDNF content and the number of BrdU positive cells was noted in the dentate gyrus, whereas opposite variations were observed in CA1, CA2 and CA3 layers, and in the arcuate and ventromedial nuclei. In the hippocampus, P15-FR50 rats showed an increased number of BrdU positive cells in all regions, whereas, at P22, a decrease was observed in the CA2. In the hypothalamus, between E21 and P8, MPU increases the number of BrdU positive cells in all regions analysed and, until P15, marked differences were noticed in the median eminence, the paraventricular nucleus and the arcuate nucleus. Taken together, the results obtained in the present study show that MPU changes the time course of production of BDNF and cell proliferation in specific hippocampal and hypothalamic areas during sensitive developmental windows, suggesting that these early perinatal modifications may have long-lasting consequences.

The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family.

Biochem Pharmacol

Sean M Davidson, Aneta E Rybka, Paul A Townsend

The urocortins are members of the corticotropin releasing hormone (CRH) family of peptide hormones. The archetypal member of this family, CRH, plays an important role in regulating thermogenesis and homeostasis by acting centrally and systemically in target organs via its two receptors CRH-R1 and CRH-R2. However, by virtue of their much greater relative affinity for CRH-R2, the physiological effects of the urocortin peptides are largely restricted to peripheral organs such as the heart. A powerful cytoprotective effect of urocortin peptide administration against ischemia and reperfusion injury has been demonstrated in isolated cardiomyocyte models, as well as in the intact heart both in vitro and in vivo. Extremely promising data has shown the beneficial effect of treating pacing-induced heart failure in sheep with urocortin molecules. Though the efficacy and specificity of these molecules in humans is not yet established, molecular dissection of the cytoprotective pathways activated by urocortin peptides suggests that the beneficial effects may be separable from potentially deleterious effects.

Response of growth and myogenic factors in human skeletal muscle to strength training.

Br J Sports Med

Y Liu, M Heinichen, K Wirth +2 more

To investigate the response to different strength training techniques of growth and myogenic factors in human skeletal muscle, with particular emphasis on satellite cell (SC) activation.

[A comparative study of noopept and piracetam in the treatment of mild and moderate cognitive impairment in patients with organic brain diseases of vascular and traumatic origin].

Zh Nevrol Psikhiatr Im S S Korsakova

G G Neznamov, E S Teleshova

[Compensatory and antiamnestic effects of heptapeptide Selank in monkeys].

Zh Evol Biokhim Fiziol

The work presents results of study of role of heptapeptide Selank--an anxiolytic from group of biologically active peptides--in compensation of disturbed psychic and homeostatic functions in monkeys. New data have been obtained which indicate that an intranasal administration of Selank produces long-term changes of the monkeys' behavior disturbed during neurosis: elimination of fear and aggression and an increase of orientational-explorative activity as well as facilitation of handling reactions and communicational relations. It has been established that on the background of the Selank there occurs a long compensation of disturbed psychic functions (processes of memory) and of homeostatic parameters. It has been shown that unlike the earlier studied neurohormones (thyroliberin and ACTH4-10), the antistressor Selank effects do not depend on the type of neurotic disturbances and have long-term compensatory character. Comparison of the data obtained on monkeys with results of similar studies on the more low-organized mammals (rodents) allow suggesting that the new peptide preparation Selank is a promising agent for correction of various psychoemotional disturbances (alarm- and depression-like disorders).

[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice].

Zh Vyssh Nerv Deiat Im I P Pavlova

K Iu Sarkisova, I I Kozlovskiĭ, M M Kozlovskaia

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

Creatine supplementation augments skeletal muscle carnosine content in senescence-accelerated mice (SAMP8).

Rejuvenation Res

Wim Derave, Glenys Jones, Peter Hespel +1 more

The histidine-containing dipeptides (HCD) carnosine and anserine are found in high concentrations in mammalian skeletal muscle. Given its versatile biologic properties, such as antioxidative, antiglycation, and pH buffering capacity, carnosine has been implicated as a protective factor in the aging process. The present study aimed to systematically explore age-related changes in skeletal muscles HCD content in a murine model of accelerated aging. Additionally, we investigated the effect of lifelong creatine supplementation on muscle HCD content and contractile fatiguability. Male senescence-accelerated mice (SAMP8) were fed control or creatine-supplemented (2% of food intake) diet from the age of 10 to 60 weeks. At week 10, 25, and 60, tibialis anterior muscles were dissected and analysed for HCD and taurine content by HPLC. Soleus and EDL muscles were tested for in vitro contractile fatigue and recovery. From 10 to 60 weeks of age, muscular carnosine (-45%), taurine (-24%), and total creatine (-42%) concentrations gradually and significantly decreased. At 25 but not at 60 weeks, oral creatine supplementation significantly increased carnosine (+88%) and anserine (+40%) content compared to age-matched control-fed animals. Taurine and total creatine content were not affected by creatine supplementation at any age. Creatine-treated mice showed attenuated muscle fatigue (soleus) and enhanced force recovery (m. extensor digitorum longus [EDL]) compared to controls at 25 weeks, but not at 60 weeks. From the present study, we can conclude that skeletal muscle tissue exhibits a significant decline in HCD content at old age. Oral creatine supplementation is able to transiently but potently increase muscle carnosine and anserine content, which coincides with improved resistance to contractile fatigue.

Galanin in Alzheimer's disease: neuroinhibitory or neuroprotective?

Cell Mol Life Sci

S E Counts, S E Perez, E J Mufson

Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.

[Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].

Zh Nevrol Psikhiatr Im S S Korsakova

A A Zozulia, G G Neznamov, T S Siuniakov +11 more

Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.

[Compensatory effect of selank on the mnestic functions disturbed by neurotoxic damage of the noradrenergic system of the rat brain].

Eksp Klin Farmakol

I I Kozlovskiĭ, Iu F Belozertsev, T P Semenova +2 more

It has been shown that the peptide anxiolytic drug Selank recovers learning and memory impaired by damage of the noradrenergic (NA) brain system in Wistar rats after injection of the NA-synthesis inhibitor disulfiram, administration of neurotoxic compound 6-OHDA, or a combined induction of hypoxic hypoxia and hypercapnia. The main component of the Selank action is the stimulation of the search reflex aimed to distinguish an adequate adaptive response in the first trials of the learning session. The enhancement of memory consolidation and retrieval shows evidence for stimulation of the brain motivation mechanisms impaired by the NA system damage.

[Genotype-dependent mice behavior in cognitive tasks. Effect of noopept].

Zh Vyssh Nerv Deiat Im I P Pavlova

A P Bel'nik, R U Ostrovskaia, I I Poletaeva

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.

Inhibiting myostatin with follistatin improves the success of myoblast transplantation in dystrophic mice.

Cell Transplant

Basma F Benabdallah, Manaf Bouchentouf, Joel Rousseau +5 more

Duchenne muscular dystrophy is a recessive disease due to a mutation in the dystrophin gene. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the myostatin signal with an antagonist, follistatin. Three different approaches were studied to overexpress follistatin in the muscles of mdx mice transplanted with myoblasts. First, transgenic follistatin/mdx mice were generated; second, a follistatin plasmid was electroporated in mdx muscles, and finally, follistatin was induced in mdx mice muscles by a treatment with a histone deacetylase inhibitor. The three approaches improved the success of the myoblast transplantation. Moreover, fiber hypertrophy was also observed in all muscles, demonstrating that myostatin inhibition by follistatin is a good method to improve myoblast transplantation and muscle function. Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy.

Discovery that a melanocortin regulates sexual functions in male and female humans.

Peptides

Mac E Hadley

Melanocortins (MCs) are multifunctional peptide hormones that regulate a diversity of physiological functions. MCs have been implicated in sexual function in animals. We document here that a MC analog, Melanotan II (MTII), can enhance sexual function in human males (erectile activity) and females (increased levels of sexual desire and genital arousal). Unlike other sexual-enhancement drugs, MTII works at the level of the brain, thus eliciting a rather natural sexual response with minimal or no undesirable side effects. The actions of the peptide were discovered accidentally while studying the effects of the peptide and related analogs on human skin pigmentation (tanning).