CNS & Neurological Disorders - Drug Targets

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CNS & Neurological Disorders - Drug Targets

ISSN: 1871-5273 eISSN: 1996-3181

Impact Factor:2.506

SCIENCE BENTHAM

Haroon Khan

^1,*

, Sumaira Khattak

¹

, Mohammad S. Mubarak

²

, Saud S. Bawazeer

³

, Tareq Abu-Izneid

³

and Mohammad A. Kamal

^4,5

1Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan; ²Department of Chemistry, The Uni- versity of Jordan, Amman, 11942, Jordan; ³Department of Pharmaceutical Sciences, Faculty of Pharmacy Umm Al- Qura University, Makkah, P.O. Box 42, Saudi Arabia; ⁴King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; ⁵Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia

A R T I C L E H I S T O R Y

Received: December 27, 2016 Revised: February 27, 2017 Accepted: February 27, 2017

DOI:

10.2174/1871527316666170731102237

Abstract: Background & Objective: Clinical depression is an unsatisfactory mood disorder affecting millions of people worldwide. The disorder is associated with a phenomenal number of suicidal attempts each year, and it has been estimated that 10-20 million people around the world made an at- tempt of suicide in some stage of the disease. Thus, medicinal intervention is ultimately required to avoid such type of extreme outcomes. There are numerous therapeutic antidepressant options in clinical practice, however, most of them face the challenge of efficacy, side effects, and patient compli- ance. In this scenario, new effective and safe therapeutic agents are becoming the major focus of researchers in the area of neuropharmacology, who and are evaluating different sources such as synthetic and natural therapeutics. Similarly, thousands of peptides have already shown vital role in human physiology for regulation of different activities.

Conclusion: This mini-review will focus on peptides with reported antidepressant activity, along with their mechanism of action. Furthermore, the present article summarizes the literature pertaining to these peptides as antidepressant agents.

Keywords: Antidepressant potential, future prospects, limitations, mechanism, peptides, therapeutic.

1. INTRODUCTION

Depression represents a condition of low mood and ha- tred to activity that can affect a person’s thoughts, behavior, feelings, and sense of well-being [1]. Major depression is a disorder that affects approximately 8% of men and 15% of women in the course of their lifetime. Depression causes great mental anguish and meddles with biological processes that regulate inflammation, coagulation, metabolism, auto- nomic function, neuroendocrine regulation, sleep, and appe- tite [2]. In addition, depressive disorders influence approximately 21% of the community worldwide [3, 4]. Depression, anxiety, and stress disorder are attributed to disturbance in the hypothalamus-pituitary-adrenal axis and corticosteroid receptor signaling [5]. Major depression is not a single disorder but can be divided to two sub groups, melancholic and atypical depression. Melancholic depression is a state of pathological hyperactive arousal and anxiety in the form of feelings of worthlessness and hopelessness [6, 7]. Further- more, in this form of depression, patients do not feel pleasure

*Address correspondence to this author at the Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan;

E-mail: [email protected]

in activities that are pleasurable to others. Moreover, melancholic depression has symptoms of anorexia, distorted timing of rest and activity, most probably due to early-morning awakening, decreased sexual interest, endocrine abnormali- ties such as hyper-cortisolism, and diurnal variation in mood [8-10]. On the other hand, a sense of disconnectedness and emptiness characterize atypical depression. The disorder often causes a large number of suicide attempts each year; it is estimated that 10-20 million people around the world at- tempt suicide [11].

The design of effective treatment for this disorder is very challenging due to low clinical efficacy of antidepressants.

Moreover, favorable effects are achieved after lengthy and extended initial treatments [12, 13]. These limitations make it necessary to search for new biological targets and drugs for treatment of depression. In this regards, several sources are under investigation to overcome reported limitations of synthetic agents extensively used for the management of various types of depressions [14]. Among these are peptides, which are the most emerging therapeutic tools for the search of new effective agents. Accordingly, this review focuses on the therapeutic ability of peptides as antidepressant agents with emphasis on their mechanism of action, and on detailed

CNS & Neurological Disorders - Drug Targets, 2018, 17, 9-13

REVIEW ARTICLE

Antidepressant Potential of Peptides: New Insights as Future Therapeutic

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studies that could lead to outstanding compounds for the treatment of various types of depressive disorders. In this context, recent references have been obtained from databases such as ScienceDirect, NCBI, Google Scholar, and Sci- Finder. We hope this review will be a valuable addition to the field, and will be a great help for researchers. Below are details about documented bioactivity of peptides and their uses for treatment of depression.

2. INSIGHTS ON PEPTIDE RESEARCH

In recent years, peptides have gained increased interest as therapeutics, though peptide research has started with the discovery of hormones and neurotransmitters, and the use peptides in hormonal disorders [15, 16]. A real boost in peptide research as drugs was observed with the discovery of 3D structures of proteins and their cellular functions. As protein- protein interaction is crucial for cellular signaling, and as their surfaces are made up of epitopes of amino acids, peptides are considered as an ideal choice in the modulation of such interactions [4]. Peptides are believed to operate by mimicking the surface of one of the proteins, hinder protein- protein interaction, and regulate the signaling [17].

Peptides are highly selective and efficacious, and at the same time, relatively safe and well tolerated. Moreover, the most attractive feature of peptide research is its low produc- tion cost compared to traditional small molecules, as these agents can be synthesized in bulk. More than 7000 naturally occurring peptides have been isolated and identified, and approximately 140 of these are in clinical trials. Indeed, these peptides exhibit the advantages of small-molecule drugs as well as protein therapeutics [18]. Furthermore, more than 60 peptide-derived drugs received marketing approval and several hundreds of novel bioactive peptides are in preclinical and awaiting clinical studies [19]. Recently, peptides have shown widespread activities as antimicrobial [20], including Candida species [21], analgesic and anti- inflammatory [22], anticancer and antitumor [23], and autoimmune diseases [24]. In this regard, designing peptides as new effective therapeutic agents is a rational approach.

3. ANTIDEPRESSANT PEPTIDES

A team of American researchers found that TRH-like peptides and TRH (pGlu- His-Pro-NH₂), exhibit multiple neurological effects such as neuroprotective, anticonvulsant, antidepressant, euphoric, anti-amnesic, and analeptic [25]. In addition, these researchers showed that synthetic Tyr-TRH was effective in the Porsolt Swim Test, and thus proposed its psychopharmaco-therapeutic properties. Naidu and coworker examined the antidepressant-like effect of NIH 11082 ((−)- (1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)- 6,7-benzomorphan hydrochloride), a benzomorphan ana- logue. These researchers employed the mouse tail-suspension test, an assay used to detect antidepressant agents, in their investigation. They demonstrated that NIH 11082 significantly decreases immobility time, with a comparable magnitude as the tricyclic antidepressant desipramine. In addition, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. These results suggest that delta opioid receptor agonists can produce significant effects in a behav-

ioral model used to screen antidepressant drugs [26]. On the other hand, other researchers discovered that cocaine- and amphetamine-regulated (CART) peptides are endogenous neurotransmitters that adjust a variety of physiological functions and can produce antidepressant effect in experimental models. These peptides can be found in brain regions and tissues which are implicated in depression, anxiety, and stress [27, 28].

CART (cocaine and amphetamine regulated transcript) peptides are endogenous neurotransmitters that are involved in a variety of physiologic functions. Research by Job and colleagues revealed that injection of CART 55-102 into the nucleus accumbens produces no effect; however, a combina- tion with cocaine was found to reduce the locomotor and rewarding properties of cocaine. Additionally, these researchers showed that humans carrying a missive mutation in the CART gene exhibit anxiety and depression, suggesting that CART peptides play a role in anxiety and depression, and that CART peptides might be endogenous antidepressants and can produce these effects in doses that are less than 1 µg [29]. Similarly, a team of Canadian researchers designed a peptide that could disturb the interaction between the D1 and D2 dopamine receptors, and thus can target ap- propriate brain areas via intranasal delivery method. These researchers demonstrated that at a concentration of ≥ 1.67 nmol/g, the D1-D2 interfering peptide evokes marked antidepressant-like effect in the forced swimming test (FST) and the overall action is comparable to that of imipramine [30].

In a recent publication, Sasaki-Hamada et al. (2015) showed that intra-cerebro-ventricular administration (i.c.v.) of glucagon-like peptide-2 (GLP-2) caused antidepressant- like action in the forced-swim test. Furthermore, these researchers found that treatment with this peptide (3 µg, i.c.v.) for 6 days has antidepressant-like effects on adrenocortico- tropic hormone (ACTH)-treated mice,

and

significantly decrease the immobility time in the FST in saline-treated and ACTH-treated mice [31]. Their results suggest that GLP-2 can act on specific brain regions to regulate stress, and can induce antidepressant-like effects under imipramine-resistant conditions, which may be associated with modulation of the hypothalamic-pituitary-adrenal-axis. Interestingly, Sun and coworkers explored the relationship between plasma Aβ42, a biomarker of Alzheimer’s disease (AD) and depression in a homebound elderly population with and without the ApoE4 allele. Their investigation involved 1060 homebound elders with ApoE characterization and depression status. Results revealed that in the absence of cardiovascular disease (CVD), lower plasma concentration of Aβ42 is observed with depressed elders. Furthermore, depressed subjects treated with antidepressant have a lower concentration of plasma Aβ40.

Taken all together, results from that investigation suggest that a relationship exists between lower Aβ42 plasma concentration and depression in the absence of CVD [32].

In a similar fashion, a group of Japanese researchers investigated the effects of wheat-derived pyroglutamyl peptides on emotional behaviors. Results revealed that pyroglu- tamyl-leucine (pyroGlu-Leu, pEL) and pyroglutamylglu- taminyl-leucine (pyroGlu-Gln-Leu, pEQL) exhibit antidepressant-like activity in the tail suspension and forced swim tests in mice. Additionally, they found that pyroglutamyl

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peptide (pEQL) has more potent activity than pEL, where it exhibits potent antidepressant-like activity after i.p. and i.c.v.

administration, and exhibits antidepressant-like activity at a lower dose than Gln-Gln-Leu. Furthermore, these researchers concluded that Tpyroglutamyl peptides may enhance hippocampal neurogenesis via a pathway independent of the brain-derived neurotrophic factor (BDNF) [33].

In a study by Mazella and colleagues, the antidepressant effects of spadin which is a secreted peptide related to the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin), was examined; spadin bound specifically to TREK-1 with an affinity of 10 nM. These workers concluded that spadin is an antidepressant of new generation with a rapid onset of action. In addition, Spadin was the first natural antidepressant peptide identified [12].

On the other hand, Tanaka and Telegdy evaluated the antidepressant-like effects of corticotropin-releasing factor (CRF) family type peptides, urocortin 1 (Ucn 1), urocortin 2 (Ucn2), and urocortin 3 (Ucn 3) (0.13, 0.25 and 0.5 µg/2 µL, i.c.v.) in mice, using a modified forced swimming test (FST).

Results revealed that Ucn 1 has no action on any of the parameters studied in the modified FST, whereas Ucn 2 and Ucn 3 produce antidepressant effects by shortening the immobility time and by increasing the climbing and swimming times. These results suggest that CRF2 receptor stimulation by Ucn 2 or Ucn 3 leads to antidepressant-like action, but dual stimulation of the CRF1 and CRF2 receptors by Ucn 1 does not activate antidepressant activity in the modified mouse FST [34].

In a paper recently published by Ehrensing, MIF-1 (pro- lyl-leucyl-glycinamide) was mentioned as a compound that

is more effective than traditional antidepressants with greater efficacy and faster onset of action [35]. On the other hand, Cerit et al. (2015) discovered that ARA290, an EPO-analog peptide, has neurotrophic and antidepressant effects. This compound lowers the recognition of happy and disgust facial expressions and increases attention towards positive emotional pictures. Furthermore, it does not display effects on mood and affective symptoms [36].

4. ANTI-DEPRESSANT MECHANISMS OF PEPTIDES Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic- pituitary-adrenal (HPA) axis. In response to stress, CRF ini- tiates a series of events that lead to the release of glucocorticoids from the adrenal cortex. Because of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response.

Melanocyte-inhibiting factor (MIF) increases c-Fos expression in the brain in regions involved in regulation of mood, anxiety, depression, and memorymigratory inhibitory [35]. On the other hand, CART (cocaine and amphetamine regulated transcript) peptides affect the hypothalamic- pituitary-adrenal (HPA) axis through corticotropin-releasing factor (CRF) activation; CRF plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. Researchers believe that the hypothalamic- pituitary-thyroid (HPT)-axis plays a role in the pathophysi- ology of depression [29]. On the other hand, the CART peptides also showed involvement of 5-hydroxytryptamine (5- Table 1. Peptides with antidepressant like activity with possible underlying mechanism(s).

S. No Peptides Mechanism of Action Indication Reference

1

TRH-like peptides (Tyr-TRH; Phe- TRH;

Leu-TRH; TRH; Val-TRH; Gln-TRH;

EEP, pyroglutamyltyroslyprolineamide)

Unknown Antidepressant, euphoric, and ana-

leptic, neuroprotective properties [25]

2 Plasma Amyloid - (Beta) Peptides Unknown Antidepressant [32]

3 NIH 11082 Delta-opioid receptor antagonist naltrindole

selectively inhibited its effect Antidepressant, antianxiety [26]

4 Urocortin 1, urocortin 2 and urocortin 3 CRF2 receptor stimulation Antidepressant [34]

5 Spadin TREK-1 inhibition Antidepressant [12]

6 CART (cocaine and amphetamine regulated transcript) peptides

Regulation of TRH and stimulates oxytocin

release Antidepressant, antianxiety [29]

7 D1–D2 interfering peptide Disrupt the interaction between D1 and D2

dopamine receptors. Antidepressant [30]

8 glucagon-like peptide-2 (GLP-2) Activation of monoamine receptors. Antidepressant [31]

9 MIF-1

MIF increased c-Fos expression in brain regions involved in the regulation of mood,

anxiety depression, and memory.

Antidepressant [35]

10 ARA290 Increase memory-relevant neural response

in the hippocampus Antidepressant [36]

11

Pyroglutamylleucine (pyroGlu-Leu, pEL) and pyroglutamylglutaminylleucine

(pyroGlu-Gln-Leu, pEQL)

Enhance hippocampal neurogenesis Antidepressant [33]

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HT) for antidepressant action. Results revealed that treatment of CART 61-102 in dorsal raphe nucleus causes a significant dose-dependent increase in 5-HT concentration, and thus exhibits antidepressant effect [37]. In case of NIH 11082 peptides, scientists found that the delta-opioid receptor antagonist naltrindole (AD₅₀ = 2.0 mg/kg), but not the non-selective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocks the effects of NIH 11082 in the tail-suspension test [26]. Moreo- ver, scientists showed that thyrotropin-releasing hormone- (TRH) has antidepressant properties. The hypothalamic- pituitary-adrenal (HPA) axis plays a role in anxiety and depression [38]. Stress activates the HPA-axis, which leads to a release of corticotrophin releasing factor (CRF). This process then stimulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which in turn stimulates the release of glucocorticoids from the adrenal glands. These events suggest that stress regulates CART expression in parts of the hypothalamus, perhaps through several mechanisms, whereas CRF regulates CART peptide release in the HPA- axis [29]. An increase in the expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and other areas in the brain caused by the dopamine D1–D2 interfering peptide, could explain the antidepressant effects of that peptide [30]. On the other hand, researchers indicated that the antidepressant-like effects of glucagon-like peptide-2GLP- may suggest that GLP-2 acts on specific regions of the brain to regulate stress conditions, and that it induces antidepressant-like effects under imipramine-resistant conditions.

These results may associate GLP-2 with the modulation of the hypothalamic-pituitary-adrenal-axis and with monoamine receptors [31].

In a similar fashion, Yamamoto and coworkers [33] investigated the effects of wheat-derived pyroglutamyl peptides on emotional behaviors in mice. These researchers found that pyroglutamyl leucine (pEL) and pyroglutamylglu- taminyl leucine (pEQL) exhibit more antidepressant-like activity than pyroglutamyl leucine (pEL). In addition, they found that both pEQL and pEL produced their antidepressant-like activity by enhancing neuronal proliferation in the hippocampus [33]. In their investigation on the antidepressant effects of spidin, Mazella and coworkers found that this glycoside specifically bound to TREK-1 with an affinity of 10 nM efficiently blocks the TREK-1 activity in COS-7 cells. In addition, the glycoside induces, in vivo, an increase in 5-hydroxytrepatamine in the dorsal Raphe nucleus (Mazella et al., 2010). Tanaka and Telegdy investigated the antidepressant-like effect of the cortisone releasing factor (CRF)-family peptides urocortin 1 (Ucn 1), urocortin2 (Uncn 2), and urocortin3 (Uncn 3) in mice. These researchers demonstrated that the peptide binds to both CRF1 and CRF2.

The CRF1 receptors participate in anxiety- and depressant- like actions. However, the role of CRF2 in anxiety behavior is not clear [34].

5. LIMITATION/CHALLENGES NEEDED TO BE ADDRESSED

Indeed, there are several indispensable challenges in the peptide-related drug discovery process and technologies that need to be address in order to get fruitful results. For in-

stance, the physical and chemical stability of peptides is a primary challenge, as they are susceptible to hydrolysis and oxidation, which will affect their therapeutic status. Simi- larly, peptides have very short half-life and are quickly eliminated from the body; this needs to be addressed through various pharmaceutical technologies. In this regard, Mar- schütz and coworker introduced a specific drug delivery system for oral administration of peptides that prevents enzymatic degradation [39], while Luca et al. (2010) suggested chemical modification (peptidomimetics) for such stability [40]. Chemical modification methods can be utilized for increasing oral bioavailability, in addition to other parameters related to therapeutic significance. Additionally, most of peptides-based therapeutics are available in parental formu- lation; therefore, oral routes need attention in future research.

CONCLUSION

Peptides have attracted the attention of researchers worldwide as anti-depressant therapeutics in recent years because of numerous limitations of synthetic drugs that are in clinical use. More than 60 peptide drugs have reached the market, and several hundreds of novel therapeutic peptides are in preclinical and clinical development. Peptides are safe, well tolerated, and potent therapeutics. Considering all of the above, we strongly believe that peptides can offer an enor- mous growth potential as future therapeutics for the treatment of depression and related disorders. In conclusion, this review reveals that peptides can be useful therapeutic agents for the treatment of depression due to their safety, and low cost relative to synthetic drugs. However, detailed studies are required to establish the safety and efficacy of these agents before they hit the market.

REVIEW CRITERIA

Original research articles were obtained via Google and SciFinder scholar with the key words including antidepressant peptides. In the preparation of this review, we selected and cited the most recent available articles.

CONSENT FOR PUBLICATION Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS Declared none.

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DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Edito- rial Department reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 28758584