Introduction
This study focus serotonin (5-HT) syndrome, the most serious toxic interaction of antidepressants (i.e., Houlihan, 2004) and attempts to further clarify an intriguing effect of a peripheral peptide, gastric pentadecapeptide BPC 157, on brain 5-HT synthesis and release (Tohyama et al., 2004). Namely, it initially reduced the duration of immobility to a greater extent than imipramine, suggestive for involvement of the brain serotonergic and noradrenergic systems (Sikiric et al., 2000). Currently, gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.1419; i.e., Sikiric et al., 1994, Sikiric et al., 1997a, Sikiric et al., 1997b, Sikiric et al., 1999, Sikiric et al., 2003, Jelovac et al., 1999, Bilic et al., 2001, Lovric-Bencic et al., 2004, Tohyama et al., 2004, Veljaca et al., 2002) is promising in inflammatory bowel disease clinical phase II (PL-10, PLD-116, PL-14736, Pliva). More importantly, besides reduced duration of immobility and particular effect on brain 5-HT synthesis (Tohyama et al., 2004, Sikiric et al., 2000), also given peripherally, it affects various disturbances supposed to be centrally mediated (Jelovac et al., 1998, Jelovac et al., 1999, Sikiric et al., 1999, Sikiric et al., 2001, Sikiric et al., 2002, Boban Blagaic et al., 2004) by the systems (i.e., dopaminergic, GABA-ergic) (Nisijima et al., 2001, Nisijima et al., 2003) involved also in 5-HT disturbances.
As indicated, very recently, using α-[14C]methyl-l-tryptophan autoradiographic measurements, gastric pentadecapeptide BPC 157, a gut peptide, given peripherally, has region specific influences on brain 5-HT synthesis in rats, different following acute and chronic treatments (Tohyama et al., 2004). The effects of BPC 157 reported (Tohyama et al., 2004) do not resemble the results obtained with any other serotonergic drug using this method (Diksic, 2001, Diksic and Young, 2001, Diksic et al., 1995, Tohyama et al., 2002). This may suggest that although BPC 157 has an effect on 5-HT synthesis in some brain structures in which 5-HT synthesis is affected by drugs acting on the brain serotonergic system (e.g., fluoxetine, paroxetine), the mechanism of the BPC 157 action probably differs greatly (Tohyama et al., 2004). Most likely, this peptide has a prompt and inherent action since it also reduces antidepressant-arrhythmias, and severe cardiotoxicity (Lovric et al., 2003, Lovric-Bencic et al., 2004). Its particular stability (i.e., no degradation in otherwise highly degradating condition (i.e., Sikiric et al., 1994, Sikiric et al., 1997a, Sikiric et al., 1997b, Sikiric et al., 1999, Sikiric et al., 2003, Jelovac et al., 1999, Lovric et al., 2003, Lovric-Bencic et al., 2004, Boban Blagaic et al., 2004), non-degraded in human gastric juice (Veljaca et al., 1995), and non-toxicity (even limit test negative, no side effects in trials (Veljaca et al., 2002)) certainly both contribute. Together, these findings could be of both theoretical and practical importance for antidepressants therapy.
Thus, in present study, presenting with a beneficial effect mostly related to a counteraction of 5-HT2A-receptor phenomena, pentadecapeptide BPC 157 (in doses previously used (Sikiric et al., 1993, Sikiric et al., 1994, Sikiric et al., 1997a, Sikiric et al., 1997b, Sikiric et al., 1999, Sikiric et al., 2000, Sikiric et al., 2002, Sikiric et al., 2003, Jelovac et al., 1998, Jelovac et al., 1999, Lovric et al., 2003, Lovric-Bencic et al., 2004, Tohyama et al., 2004, Boban Blagaic et al., 2004) particularly counteracts a severe 5-HT syndrome otherwise induced with pargyline (irreversible monoamine oxidase (MAO)-inhibition)/l-tryptophan (5-HT precursor) application (i.e., rats presented with fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia).
Section snippets
Animals
Male Wistar rats aged 35 days weighing 150 g were used in all of the experiments accordingly with study of Darmani and Ahmad (1999), randomly assigned. The rats where housed at a room temperature of 22 °C ± 1–2 °C with a 12-h light–dark cycle singly caged, for 14 days before the experiment. Food and water were available ad libitum. Local ethic committee approved all of the experiments.
Drugs
Pargyline HCl (Sigma, USA) and pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, molecular weight 1419 Da, manufactured
Results
Consistently with 5-HT-syndrome induction (irreversible MAO-inhibition + 5-HT precursor), pargyline before l-tryptophan, produce together a severe disorder, a full 5-HT syndrome in rats (fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia; Fig. 1 and Table 2). Given separately, l-tryptophan as a 5-HT precursor produces no change (Fig. 2), while pargyline, as an irreversible MAO-inhibitor, induces only mild disturbances, i.e., hypothermia and feeble hind
Discussion
Gastric pentadecapeptide BPC 157 particularly counteracts 5-HT syndrome (i.e., otherwise induced by combining irreversible MAO-inhibition (pargyline) and 5-HT precursor (l-tryptophan; Darmani and Ahmad, 1999, Abdel-Fattah et al., 1997)). This emphasizes all of its effects reported: brain 5-HT synthesis and release (Tohyama et al., 2004), the duration of immobility reduced to a greater extent than imipramine (Sikiric et al., 2000) with other central effects (i.e., given in the same dose range (