Introduction
We focused on the application of the stable gastric pentadecapeptide BPC 157 [
1‐
11] to improve the outcomes of spinal cord injury in rats.
Spinal cord injury generally involves the preclusion of neural relays across the lesion site and is thereby predictably associated with a lack of functional improvement [
12,
13]. On the other hand, there is evidence that spinal cord injury triggers a cascade of secondary degenerative events that cause further damage to the injured area and induce local inflammation along with hemorrhage and edema [
12,
13] and that the therapeutic agents imatinib (which has been shown to inhibit cytokine production and reduce hemorrhage, edema, and inflammation) [
14] and ibuprofen initiate favorable axonal growth and functional recovery through Rho inhibition [
15]. Likewise, there is favorable evidence to support the engraftment of neural stem cells [
16] or bone marrow stromal cells [
17] into the lesion site. However, there are disputes about the relevant applicability of this evidence [
18,
19], particularly considering the low survival rate of bone marrow stromal cells transplanted into the contused adult rat spinal cord [
20,
21] and the need to completely fill the lesion site with neural stem cells [
22]. Consequently, there have been attempts to improve the therapeutic effectiveness with combined treatments (i.e., neural stem cells with fibrin and a growth factor cocktail (BDNF; NT-3; mGDNF; IGF; bFGF; EGF; PDF; aFGF; and HGF) [
23] or bone marrow stromal cells with the application of cyclosporine, minocycline, and methylprednisolone [
24]). Likewise, considering the beneficial effect of the deletion of the Nogo Receptor 1 (NgR1) gene, a sequential combination of Nogo-A suppression (by anti-Nogo-A antibody treatment) and treadmill rehabilitative training was examined [
25].
It is generally believed that further attempts are fully justified [
26]. In comparison, the stable gastric pentadecapeptide BPC 157, an emerging treatment with potential therapeutic applications, appears to be unrestricted by the limitations seen in previous therapies. The stable gastric pentadecapeptide BPC 157, an original cytoprotective antiulcer peptide that is used in ulcerative colitis and recently in a multiple sclerosis trial and that has an LD1 that has not been achieved [
1‐
11], is known to have pleiotropic beneficial effects [
1‐
11] and to interact with several molecular pathways [
2,
27‐
32]. BPC 157 has beneficial effects on inflammation, hemorrhage, and edema after traumatic brain injury [
33], various severe encephalopathies (which follow gastrointestinal and/or liver lesions), NSAID overdose [
34‐
37], or insulin overdose seizures [
38] and on severe muscle weakness after exposure to the specific neurotoxin cuprizone in a rat multiple sclerosis model [
39] or magnesium overdose [
40]. In other studies, it was shown that BPC 157 counteracts increased levels of proinflammatory and procachectic cytokines such as IL-6 and TNF-α [
2]. Finally, BPC 157 improves sciatic nerve healing [
41] when applied intraperitoneally, intragastrically, or locally at the site of anastomosis shortly after injury or directly into the tube after non-anastomosed nerve tubing (7-mm nerve segment resection).
Therefore, we used a model of spinal cord injury that has many characteristics found in human spastic syndrome [
42] and can be used long-term to provide a realistic model of spasticity development in the tail muscle.
The administered therapy was a one-time intraperitoneal application of the stable gastric pentadecapeptide BPC 157, much like the one-time engraftment of neural stem cells [
16] or bone marrow stromal cells [
17] into the lesion site. This experiment will provide evidence that BPC 157 treatment can recover tail function, resolve spasticity, and improve neurologic recovery.
Discussion
This study attempted to demonstrate that the application of the stable gastric pentadecapeptide BPC 157 (by either of the used regimens) can improve the symptoms of spinal cord injury and lead to functional recovery in rats. In general, the one-time intraperitoneal application of the stable gastric pentadecapeptide BPC 157 is much like the engraftment of neural stem cells [
16] or bone marrow stromal cells [
17] into the lesion site. One should consider the primary phase lesion and hemorrhaging that results from mechanical damage during SCI as well as the secondary phase lesion that lasts several hours or even several months and is accompanied by edema, hemorrhage, inflammation, and cytotoxic edema [
44‐
47] and may extend to the white matter area and lead to white matter degeneration and damage [
48,
49]. This substantiates the evidence that the spared white matter holds the key to the functional motor recovery of the hind limbs after SCI and is closely correlated with the functional restoration of the paralyzed hind limbs [
50‐
52]. On the other hand, spontaneous and often substantial functional improvements [
53‐
55] after partial lesioning of the spinal cord are associated with the spontaneous sprouting of axons in the corticospinal tract [
56‐
58] and the formation of neural circuits by spared spinal cord tissue [
26]; these processes lead to partial functional recovery [
59] or the formation of the neural fiber connection between the central pattern generator (CPG) and interneurons in the spinal cord, which can enable rhythmic movement [
60‐
62].
Thus, to illustrate these combining points (i.e., [
13,
44,
63]), considering that white matter injury is the major cause of functional loss after SCI [
45,
52], it is important to note that cysts and the loss of axons instead of hemorrhagic areas were observed in the white matter in all of the controls beginning on day 7 and that the rats exhibited a tail motor score that persisted with only small improvements, sustained debilitation, sustained tail spasticity until the end of the experiment (day 360), a decrease in the number of large myelinated axons in the caudal nerve, a higher MUP (giant potential) in the tail muscle, and a group of atrophic fibers that likely represented a large unit that acquired many fibers through collateral reinnervation and then degenerated. Autotomy that occurs long after injury may appear as pain that occurs below the level of the injury (below-level pain) [
64,
65], and the late spontaneous worsening may be the result of complete deafferentation of one or several spinal segments the stimulation of the nerve plexus, or dorsal root injury [
66]. Together, these findings illustrate definitive spinal cord injury with very small spontaneous improvements in functional loss.
In contrast, it is possible that the administration of BPC 157 counteracts these disturbances to lead to considerable functional recovery. The vacuoles and the loss of axons in the white matter were largely counteracted in BPC 157-treated rats (Table
1 and Fig.
3). This result suggests that BPC 157-treated rats exhibit continual improvement in motor function even before tissue recovery, as observed by microscopy assessment. The resolution of spasticity by day 15 (Fig.
2) suggests that BPC 157 administration prevents the chain of events after spinal cord injury that is mediated by the loss of local segmental inhibition and/or by an increased sensory afferent drive that results in the exacerbation of α-motoneuron activity [
66]. These findings substantiate the number of large myelinated axons in the caudal nerve and the lower MUP in the tail muscle.
Likewise, autotomy was completely prevented, much like in a previous study that showed recovery in BPC 157-treated rats that underwent traumatic nerve injury [
41]; this suggests the counteraction of the chain of events that otherwise leads to painful sensations and refers to denervated regions and the preservation of one or more spinal segments [
41].
It is possible that BPC 157 may affect voltage-gated sodium channels (VGSCs), which play a major role in the generation and propagation of action potentials in primary afferents [
67].
The abnormal processing of sensory inputs in the CNS [
68]. Moreover, evidence that the compromised white matter integrity of specific spinal pathways has been linked to clinical disability [
69‐
71], and cortical reorganization [
72] should be considered in relation to the pleiotropic beneficial effect of BPC 157 administration observed in distinctive brain areas and lesions [
32‐
40]. These beneficial effects include the counteractions of traumatic brain injury and severe encephalopathies after NSAID overdose, insulin overdose, magnesium overdose, and exposure to the neurotoxin cuprizone in a rat model of multiple sclerosis [
33‐
41]. These beneficial effects may be due to the formation of detour circuits—which encompass spared tissue surrounding the lesion—and could reconnect locomotor circuits [
69], thus enabling afferent inputs to be processed and conveyed to the cortex [
73] and improving spinal reflexes, even below the injury [
74].
Much like in the rats that underwent spinal cord injury recovery, rats with other disorders that are treated with BPC 157 maintain functional abilities that are otherwise impaired; for example, consciousness is maintained after brain trauma, and BPC 157 counteracts seizures, catalepsy akinesia, and severe muscle weakness [
33‐
41,
75,
76]. The effect of BPC 157 on muscle function is combined with the counteraction of increased levels of pro-inflammatory and pro-cachectic cytokines and of downstream pathways to abolish muscle cachexia [
2]. Likewise, BPC 157 ameliorates healing and recovers the impaired function of severely injured muscles that otherwise fail to spontaneously heal and plays a role after complete transection, crush, and denervation injuries [
77‐
80] and after succinylcholine intramuscular application, muscle lesion, neuromuscular junction failure, fasciculations, paralysis, and hyperalgesia [
81]. Likewise, given that the gray matter is particularly vulnerable during the primary phase [
44,
63], we should note that, from day 7, the controls presented with edema and the loss of motoneurons in the gray matter, disturbances that were largely counteracted in BPC 157-treated rats (Table
2 and Fig.
4).
In summary, this effect may be the cause or a consequence of the beneficial effects of BPC 157 on related disturbances [
1‐
11]. As demonstrated, BPC 157 counteracts free radical formation and free radical-induced lesions [
32,
82‐
84]. An interesting point would be the use of the same dose range in BPC 157 studies [
1‐
11]. Finally, further studies should clarify the molecular pathways involved and extend the one-time application (much like the engraftment of neural stem cells [
16] or bone marrow stromal cells [
17] into the lesion site) to the continuous application for the recovery of pre-existing spinal cord injury.
In conclusion, this manuscript tried to prove the therapeutic effects of BPC 157 in spinal cord injury using a rat model. Spinal cord injury recovery was achieved in BPC 157-treated rats, meaning that this therapy affects the acute, subacute, subchronic, and chronic stages of the secondary injury phase. Thus, despite the limitations of rat studies, the results showed that treatment with BPC 157 led to the recovery of tail function and the resolution of spasticity and improved the neurologic recovery; thus, BPC 157 may represent a potential therapy for spinal cord injury.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.