Introduction
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, but lacks clinically proven effective management with neuroprotective agents to limit pathophysiologic cascades or enhance repair. The enormous burden of TBI, however, clearly supports the need for such neuroprotective agents. Several peptide growth factors were found to be effective [1], [2].
Thereby, we focus on a so far not investigated peptide therapy for traumatic brain injury. We attempted to achieve a counteraction of these events by the stable gastric pentadecapeptide BPC 157 [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40] (GEPPPGKPADDAGLV, MW 1419, a small anti-ulcer peptide protecting endothelium [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [16], [17] that may also affect many central disturbances [16], [17], [18], [19], [20], [21], [22] and NO-system [4], [13], [15], [19] and act as free radical scavenger [36], efficient in inflammatory bowel disease trials (PL 14736) [23], [24] and various wound treatment [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], no toxicity reported [23], [24]). Interestingly, it was an effective therapy of muscle crush injury in rats [34], [35]. The significance and the possible role of this peptide stable in human gastric juice in the gastrointestinal tract were recently emphasized [37], [38], [39], [40].
Particularly, as an agent with neuroprotective properties [5], it both protected somatosensory neurons against capsaicin neurotoxicity and restored their function [5]. Likewise, pentadecapeptide BPC 157 particularly attenuated neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damage, including mortality [16] (of note, neuroprotection by immunophillin ligands lack the effect on MPTP-toxicity 41), significantly affected the dopamine system [16], [17], [18] (a system also implicated in the traumatic brain injury course) [42] and prevented/reversed catalepsy or stereotypy due to central dopamine system failure induced by various procedures [16], [17], [18]. Accordingly, regional serotonin synthesis in the rat brain, assessed by α-methyl-l-tryptophan autoradiographic measurements showed that, BPC 157 given peripherally may readily cross the blood–brain barrier, affect region-specific brain 5-HT synthesis in rats leading to significantly increased synthesis in the substantia nigra (compacta and reticulata) structure and counteract serotonin syndrome [21], [22]. Also, in addition to several other effects of BPC 157 (such as counteraction of acute and chronic gastric lesions, blood pressure modulation and prevention/reversal of chronic heart failure), BPC 157's antagonization of acute and chronic ethanol intoxication was found to be an effect that is at least partly NO-dependent [4], [13], [15], [19].
Thereby, following TBI, we attempted to highlight the possible beneficial effects of pentadecapeptide BPC 157 in preventing immediate unconsciousness and death during the earliest post-injury period. Then, at 24 h after injury, in surviving mice subjected to TBI, we described the attenuating effect of BPC 157 on the intensity and distribution of traumatic lesions (subarachnoidal and intraventricular haemorrhage, brain laceration, haemorrhagic laceration) and consecutive brain edema.
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Section snippets
Animals
Male, Albino NMRI (25–30 g) Hanover mice, were used in all of the experiments approved by the Local Ethic Committee, assessed by observers unaware about the given treatment. Animals were housed in air-conditioned rooms (T = 22+/−2 °C; relative humidity: 55–65%) with a light–dark cycle of 12 h:12 h (light from 0700 to 1900 h) and food and water available ad lib.
Drugs
Medication, without carrier or peptidase inhibitor, includes pentadecapeptide BPC 157 (a partial sequence of human gastric juice protein BPC,
Immediate assessment
Commonly, the applied TBI procedures (force impulses of 0.068 N s, 0.093 N s, 0.113 N s, 0.130 N s, 0.145 N s, and 0.159 N s, injury severity i–vi) produced unconsciousness as well as fatal outcomes. Elevation of height was in correlation with the gradually increased severity of produced TBI (Table 3).
In general, presenting as the improved conscious/unconscious/death ratio in TBI-mice, the pentadecapeptide BPC 157 regimens resulted with marked attenuation and improved early outcome. The improved
Discussion
We reported a consistent (clinical and microscopical) beneficial effect of BPC 157 in mice after traumatic brain injury with an escalating severity, as noted in Section 2. This was backed by the consistent injury course (i.e., instant unconsciousness (absence of the righting reflex) and death, postponed deleterious outcome presented by prominent brain edema, numerous, variably sized haemorrhagic traumatic lacerations, subarachnoidal and intraventricular haemorrhage frequently resulting with
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