Innate Vascular Failure by Application of Neuroleptics, Amphetamine, and Domperidone Rapidly Induced Severe Occlusion/Occlusion-like Syndromes in Rats and Stable Gastric Pentadecapeptide BPC 157 as Therapy

Even before behavioral disturbances, neuroleptics, amphetamine, and domperidone application rapidly emerged severe occlusion/occlusion-like syndrome, shared innate vascular and multiorgan failure in rats, comparable to occlusion/occlusion-like syndrome described with vessel(s) occlusion or similar noxious procedures application. As therapy, i.e., activation of the collateral pathways, “bypassing key” (activated azygos vein pathway, direct blood flow delivery), the stable gastric pentadecapeptide BPC 157 is a novel solution. Recently, BPC 157 therapy particularly counteracted neuroleptic- or L-NAME-induced catalepsy, lithium intoxication, and schizophrenia positive and negative symptoms (amphetamine/methamphetamine/apomorphine/ketamine). In rats with complete calvariectomy, medication (BPC 157 10 µg/kg, 10 ng/kg ip or ig) was given 5 min after distinctive dopamine agents (mg/kg ip) (haloperidol (5), fluphenazine (5), clozapine (10), risperidone (5), olanzapine (10), quetiapine (10), or aripiprazole (10), domperidone (25), amphetamine (10), and combined amphetamine and haloperidol) and assessed at 15 min thereafter. All neuroleptic-, domperidone-, and amphetamine-induced comparable vascular and multiorgan failure severe syndrome was alleviated with BPC 157 therapy as before major vessel(s) occlusion or other similar noxious procedures. Specifically, all severe lesions in the brain (i.e., immediate swelling, hemorrhage), heart (i.e., congestion, arrhythmias), and lung (i.e., congestion, hemorrhage), as well as congestion in the liver, kidney, and gastrointestinal (stomach) tract, were resolved. Intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were attenuated or eliminated. BPC 157 therapy almost annihilated arterial and venous thrombosis, peripherally and centrally. Thus, rapidly acting Virchow triad circumstances that occur as dopamine central/peripheral antagonists and agonist essential class-points, fully reversed by BPC 157 therapy, might be overwhelming for both neuroleptics and amphetamine.


Heart
Considerable myocardial congestion was commonly noted in all the control rats, in particular in those challenged with haloperidol, fluphenazine, clozapine, and quetiapine. Contrarily, in rats treated with BPC 157, these lesions were markedly attenuated or even completely annihilated in rats challenged with fluphenazine, amphetamine, and amphetamine combined with haloperidol.

Lung
Considerable lung parenchyma congestion was commonly noted in all the control rats. In particular, prominent intra-alveolar hemorrhage occurred in those challenged with risperidone, amphetamine, and combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild congestion) or even completely annihilated in the rats challenged with fluphenazine and combined amphetamine and haloperidol.  Brain (a, B). Control (a). A pronounced edema and congestion were visible affecting the cerebrum, and more prominent intracerebral cortical hemorrhage involving larger areas of cerebral brain tissue affecting the neocortex (rectangular areas). BPC 157 (B). Only mild edema and congestion were found, with small, focal, and superficial areas of neocortical hemorrhage (rectangular areas). Heart (c, D). Control (c). Moderated myocardial congestion (black arrows). BPC 157 (D). No changes were found. Lung (e, F). Control (e). A marked congestion of the lung parenchyma with intra-alveolar hemorrhage (black arrows). BPC 157 (F). Only mild lung congestion (black arrow). Liver (g, H). Control (g). A moderate dilatation and congestion of blood vessels in the portal tracts, central veins, and sinusoids (black arrows). BPC 157 (H). No changes were found. Kidney (i, J). Control (i). A marked dilatation of blood vessels and congestion in the kidney tissue, as well as glomeruli, was found (black arrows). BPC 157 (J). Mild dilatation of blood vessels and congestion in the kidney tissue, as well as glomeruli (black arrows). Gastrointestinal lesion (k, L). Control (k). Mild congestion of the stomach wall (black arrows). BPC 157 (L). No changes were found in the stomach wall. HE; magnification 100× (c, D, e, F, g, H, i, J, k, L), magnification 200× (a, B).

Heart
Considerable myocardial congestion was commonly noted in all the control rats, in particular in those challenged with haloperidol, fluphenazine, clozapine, and quetiapine. Contrarily, in rats treated with BPC 157, these lesions were markedly attenuated or even completely annihilated in rats challenged with fluphenazine, amphetamine, and amphetamine combined with haloperidol.

Lung
Considerable lung parenchyma congestion was commonly noted in all the control rats. In particular, prominent intra-alveolar hemorrhage occurred in those challenged with risperidone, amphetamine, and combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild congestion) or even completely annihilated in the rats challenged with fluphenazine and combined amphetamine and haloperidol.

Liver
Considerable dilatation and congestion of blood vessels in the portal tracts, central veins, and sinusoids were found in all the control rats, in particular in those challenged with fluphenazine, risperidone, olanzapine, quetiapine, aripiprazole, and combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild dilatation and congestion) or even completely annihilated in the rats challenged with haloperidol, aripiprazole, and amphetamine.

Kidney
Considerable dilatation and congestion in the tissue, as well as glomeruli, occurred in all the control rats, in particular in those challenged with quetiapine, aripiprazole, domperidone, and amphetamine. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild dilatation and congestion) or even completely annihilated in the rats challenged with haloperidol, aripiprazole, and amphetamine.

Gastrointestinal Lesions
Marked stomach hemorrhagic lesions, gross ( Figure 15) and microscopic, and considerable congestion of the stomach wall occurred in all the control rats, in particular in those challenged with combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, there were no gross lesions nor microscopic congestion of the stomach wall. Considerable dilatation and congestion of blood vessels in the portal tracts, central veins, and sinusoids were found in all the control rats, in particular in those challenged with fluphenazine, risperidone, olanzapine, quetiapine, aripiprazole, and combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild dilatation and congestion) or even completely annihilated in the rats challenged with haloperidol, aripiprazole, and amphetamine.

Kidney
Considerable dilatation and congestion in the tissue, as well as glomeruli, occurred in all the control rats, in particular in those challenged with quetiapine, aripiprazole, domperidone, and amphetamine. Contrarily, in the rats treated with BPC 157, these lesions were markedly attenuated (only mild dilatation and congestion) or even completely annihilated in the rats challenged with haloperidol, aripiprazole, and amphetamine.

Gastrointestinal Lesions
Marked stomach hemorrhagic lesions, gross ( Figure 15) and microscopic, and considerable congestion of the stomach wall occurred in all the control rats, in particular in those challenged with combined amphetamine and haloperidol. Contrarily, in the rats treated with BPC 157, there were no gross lesions nor microscopic congestion of the stomach wall.

A Perilous Syndrome Occurred Centrally Brain Lesions, Cerebral and Cerebellar Cortex, Hypothalamus/Thalamus, and Hippocampus
We assumed a failed common clue (i.e., intracranial (superior sagittal sinus), portal, and caval hypertension, aortal hypotension, progressed thrombosis, peripherally and centrally, failed collateral recruitment, disturbed ECG presentation, peripheral organ lesions). Namely, all the dopamine agents (haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, aripiprazole, domperidone, amphetamine, and amphetamine combined with haloperidol) converge to the similar brain lesion as well. Already in the immediate post-application period, there was increased intracranial (superior sagittal sinus) hypertension, along with the brain being consistently swollen, severe brain edema and congestion, and prominent intracerebral cortical hemorrhage. Contrarily, BPC 157 therapy reduced intracranial (superior sagittal sinus) hypertension (and eliminated portal and caval hypertension), along with counteracted brain swelling (Figure 16), markedly counteracted brain edema and congestion, and counteracted hemorrhage. Furthermore, the rats challenged with amphetamine as well as the rats challenged with haloperidol were similarly cured with BPC 157 therapy applied intragastrically and BPC 157 therapy applied intraperitoneally, providing beneficial effects that might be equally achieved by either regimen (data not specifically shown).
Pharmaceuticals 2023, 16, x FOR PEER REVIEW Figure 15. Illustrative presentation of stomach lesions in the control rats (italic small letters) and lack of stomach lesions in the BPC 157-treated rats (italic capital letters) at 15 min following application of amphetamine (AM) (a,B) or olanzapine (O) (c,D).

Brain Lesions, Cerebral and Cerebellar Cortex, Hypothalamus/Thalamus, and Hippocampus
We assumed a failed common clue (i.e., intracranial (superior sagittal sinus), portal, and caval hypertension, aortal hypotension, progressed thrombosis, peripherally and centrally, failed collateral recruitment, disturbed ECG presentation, peripheral organ lesions). Namely, all the dopamine agents (haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, aripiprazole, domperidone, amphetamine, and amphetamine combined with haloperidol) converge to the similar brain lesion as well. Already in the immediate post-application period, there was increased intracranial (superior sagittal sinus) hypertension, along with the brain being consistently swollen, severe brain edema and congestion, and prominent intracerebral cortical hemorrhage. Contrarily, BPC 157 therapy reduced intracranial (superior sagittal sinus) hypertension (and eliminated portal and caval hypertension), along with counteracted brain swelling (Figure 16), markedly counteracted brain edema and congestion, and counteracted hemorrhage. Furthermore, the rats challenged with amphetamine as well as the rats challenged with haloperidol were similarly cured with BPC 157 therapy applied intragastrically and BPC 157 therapy applied intraperitoneally, providing beneficial effects that might be equally achieved by either regimen (data not specifically shown). Figure 16. Brain presentation before the challenge, after the challenge (haloperidol or amphetamine) application, and after the therapy application. Normal brain presentation (normal small letters) and brain swelling (italic small letters) upon noxious agent (haloperidol (upper) or amphetamine (lower)) application (italic small letters) and counteracted brain swelling after BPC 157 application (italic capital letters). Upper. Brain presentation in the normal healthy rat (a), brain swelling presentation immediately upon haloperidol application (b), decreased brain swelling immediately upon BPC 157 administration (C), and decreased brain swelling in BPC 157 treated rat immediately before sacrifice (D). Lower. Brain presentation in the normal healthy rat (e), brain swelling presentation immediately upon amphetamine application (f), decreased brain swelling immediately upon BPC 157 administration (G), and decreased brain swelling in BPC 157 treated rat immediately before sacrifice (H). A similar presentation occurred also with other dopamine agents' applications and BPC 157 therapy. Figure 16. Brain presentation before the challenge, after the challenge (haloperidol or amphetamine) application, and after the therapy application. Normal brain presentation (normal small letters) and brain swelling (italic small letters) upon noxious agent (haloperidol (upper) or amphetamine (lower)) application (italic small letters) and counteracted brain swelling after BPC 157 application (italic capital letters). Upper. Brain presentation in the normal healthy rat (a), brain swelling presentation immediately upon haloperidol application (b), decreased brain swelling immediately upon BPC 157 administration (C), and decreased brain swelling in BPC 157 treated rat immediately before sacrifice (D). Lower. Brain presentation in the normal healthy rat (e), brain swelling presentation immediately upon amphetamine application (f ), decreased brain swelling immediately upon BPC 157 administration (G), and decreased brain swelling in BPC 157 treated rat immediately before sacrifice (H). A similar presentation occurred also with other dopamine agents' applications and BPC 157 therapy.

Perilous Syndrome with Concomitant Application of the Dopamine Antagonist (Haloperidol) and Dopamine Agonist (Amphetamine)
Application of haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, aripiprazole, domperidone, amphetamine, and combined amphetamine and haloperidol all produced similar portal and caval hypertension, aortal hypotension, superior sagittal sinus hypertension, progressed thrombosis, organ lesions, and considerable but distinctive ECG disturbances (i.e., prolonged QTc intervals (antipsychotics, domperidone), short QTc intervals (amphetamine)). Thereby, an unusual parallel activity of haloperidol and amphetamine (providing opposite effects of dopamine antagonists and dopamine agonists) occurred, probably beyond the dopamine system since, generally, given together, haloperidol and amphetamine did not antagonize each other, and the complete syndrome remained (Figures 17 and 18). However, in particular with ECG disturbances, some mutual antagonization might occur; prolonged PQ intervals and opposite QTc intervals might antagonize each other (while tachycardia remained) (Table 3). However, these were all consistently antagonized by BPC 157 application.
In summary, after BPC 157 therapy, the occlusion/occlusion-like syndrome course was markedly attenuated/eliminated in all rats. These occurred with haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, aripiprazole, domperidone, amphetamine, and amphetamine and haloperidol combined. These rats exhibited no portal and caval hypertension, ameliorated aortal hypotension, markedly attenuated superior sagittal sinus hypertension, attenuated tachycardias, and had not changed PQ interval or QTc interval. Additionally, venous and arterial thrombosis was attenuated, both peripherally and centrally, reduction of the brain and internal organs lesions in the heart, lung, liver, kidney, and gastrointestinal tract. Thus, BPC 157 therapy, given in either of regimens (µg, ng, ip, ig) counteracted the adverse effects that would otherwise consistently appear along with the large range of the distinctive dopamine agonists, dopamine antagonists, central (antipsychotics), peripheral (prokinetic, domperidone), and agonist (amphetamine). Note, there is the uniformity of these adverse effects obtained with distinctive dopamine agents application, dopamine antagonists, central (antipsychotics), peripheral (prokinetic, domperidone), and agonist (amphetamine). Likewise, there is evidence that these shared disturbances sustainably appeared even with the combination of amphetamine and haloperidol (agonist and antagonist do not inhibit each other effect). This suggests that the consistent antagonization exerted by the BPC 157 therapy probably takes place also beyond the dopamine system. The key finding of an activated particular collateral pathway, i.e., the azygos vein, which combined the inferior caval vein and left superior vein to reorganize blood flow, might be responsible for the noted beneficial effects.  , H), and superior mesenteric vein (violet arrows) and inferior caval vein (blue arrows) (ICVSMV) (i, J). These changes occurred probably beyond the dopamine system since given together haloperidol and amphetamine did not antagonize each other effect, and the complete syndrome remained. However, it was consistently antagonized by BPC 157 application. In summary, after BPC 157 therapy, the occlusion/occlusion-like syndrome course was markedly attenuated/eliminated in all rats. These occurred with haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, aripiprazole, domperidone, amphetamine, and amphetamine and haloperidol combined. These rats exhibited no portal and caval hypertension, ameliorated aortal hypotension, markedly attenuated superior sagittal sinus hypertension, attenuated tachycardias, and had not changed PQ interval or QTc interval. Additionally, venous and arterial thrombosis was attenuated, both peripherally and centrally, reduction of the brain and internal organs lesions in the heart, lung, liver, kidney, and gastrointestinal tract. Thus, BPC 157 therapy, given in either of regimens (µg, ng, ip, ig) counteracted the adverse effects that would otherwise consistently appear along with the large range of the distinctive dopamine agonists, dopamine antagonists, central (antipsychotics), peripheral (prokinetic, domperidone), and agonist (amphetamine). Note, there is the uniformity of these adverse effects obtained with distinctive dopamine agents application, dopamine antagonists, central (antipsychotics), peripheral (prokinetic, domperidone), and agonist (amphetamine). Likewise, there is evidence that Figure 18. Amphetamine and haloperidol-rats (amphetamine+haloperidol). Illustrative microscopic presentation of the brain (a, B), heart (c, D), lung (e, F), liver (g, H), kidney (i, J), and stomach (k, L) in the saline-treated rats (control, italic small letters) and BPC 157-treated rats (italic capital letters) at the end of the experiments at the 15 min. Brain (a, B). Control (a). A pronounced edema and congestion were visible affecting the cerebrum, and more prominent intracerebral cortical hemorrhage involving larger areas of cerebral brain tissue affecting the periventricular area (rectangular areas). BPC 157 (B). Only mild edema and congestion were found, with small, focal, and superficial areas of periventricular hemorrhage (rectangular areas). Heart (c, D). Control (c). Marked myocardial congestion (black arrows). BPC 157 (D). No changes were found. Lung (e, F). Control (e). A marked congestion of the lung parenchyma with intra-alveolar hemorrhage (black arrows). BPC 157 (F). No changes were found. Liver (g, H). Control (g). A marked dilatation and congestion of blood vessels in the portal tracts, central veins, and sinusoids (black arrows). BPC 157 (H). No changes were found. Kidney (i, J). Control (i). A moderate dilatation of blood vessels and congestion in the kidney tissue, as well as glomeruli, was found (black arrows). BPC 157 (J). Mild dilatation of blood vessels and congestion in the kidney tissue, as well as glomeruli (black arrows). Gastrointestinal lesion (k, L). Control (k). A marked congestion of the stomach wall (black arrows). BPC 157 (L). No changes were found in the stomach wall. HE; magnification 100× (c, D, e, F, g, H, i, J, k, L), magnification 200× (a, B).

Discussion
The important issue of brain-gut and gut-brain axes (mal)functioning [1] is in general focus throughout the research community. As a new practical point, we revealed the full new topic and essential matching of central and peripheral occlusion/occlusion-like syndrome with haloperidol, fluphenazine, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, domperidone, amphetamine, and combined amphetamine and haloperidol, and all particularities. These shared disturbances were consistently reversed by the stable gastric pentadecapeptide BPC 157 (i.e., activated azygos vein, direct blood flow delivery to re-establish reorganized blood flow) [1]. There, the consistent disturbance, as the effects of a multitude of agents, might be overwhelmed by the consistent effects of BPC 157 regimens (µg-ng, intraperitoneal, intragastric, given at 5 min after dopamine agents). Thus, the consistent disturbances, and the consistent therapy effects, both support each other effect (i.e., probably also in relationships that they are supposed to mimic (i.e., catalepsy, schizophrenia symptoms [28,29])). The whole disturbance was analogous to the occlusion/occlusion-like syndrome in rats with permanent occlusion of the major vessel(s) peripherally [14][15][16] or centrally [18] and similar noxious procedures [20][21][22][23][24] severely damaging endothelial function. Likewise, BPC 157 therapy effect was the same resolving multicausal pathology. There, in rats, which were damaged, several important aspects of rapidly progressing disturbances should be further analyzed. These imply brain lesions (widespread hemorrhage), heart (congestion and infarctions), lung (hemorrhage), congestion in the liver, kidney, and gastrointestinal tract, arrhythmias, and intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Disabled were major vessels (i.e., congested inferior caval vein and superior mesenteric vein, collapsed azygos vein). Arterial and venous thrombosis were peripherally and centrally, and widespread Virchow triad circumstances were generally presented.
In the timeline, the instant onset of the occlusion/occlusion-like syndrome (and the BPC 157 therapy effect as well) preceded the period where the behavioral disturbances may appear. This may be important for the given evidence that BPC 157 therapy also counteracted the neuroleptic-or L-NAME-induced catalepsy, and the schizophrenia positive and negative symptoms (amphetamine, apomorphine, methamphetamine, ketamine) [25][26][27][28][29]. Thus, we can argue with BPC 157 as a prototype cytoprotective agent [1-7] (i.e., activation of collateral (azygos vein) pathway as an outbreak of the endothelium protection long ago recognized as an innate effect of cytoprotective agents) novel common therapy solution within the new cytoprotection issue. This may imply the various typical and atypical neuroleptics-, amphetamine-, prokinetic domperidone-induced disturbances, acting centrally and/or peripherally, thus disturbances in general. Presenting the agents' supposed major activity (central (neuroleptics) [55][56][57], peripheral (domperidone) [58], peripheral and central (amphetamine) [59]) this may be whatever the occlusion/occlusion-like syndrome occurred from centrally (i.e., neuroleptics), or from the periphery (i.e., domperidone) or simultaneously at the peripheral and central sides (i.e., amphetamine). Note, rats with the occluded superior mesenteric vein, occluded superior mesenteric artery, or both artery and vein, immediately presented intracranial (superior sagittal) hypertension in addition to portal and caval hypertension and aortal hypotension [14][15][16]. Likewise, rats with occluded superior sagittal sinus, in addition to intracranial (superior sagittal sinus) hypertension immediately presented also portal and caval hypertension and aortal hypotension [18]. Consistently, in these experiments, BPC 157 might equally act given centrally topically (i.e., at the brain) or given peripherally, intraperitoneally, or intragastrically [18]. This might be three body cavities interconnected and rapidly communicating with each other, and disturbances rapidly transmitted through the venous system, unless rapidly upgraded by the given therapy [14][15][16]18,[20][21][22][23][24]. This was especially evidenced in rats with permanent mechanically maintained severe intra-abdominal hypertension, grade III and IV. Receiving BPC 157 therapy provided that rats smoothly sustained intra-abdominal hypertension, even grade III and IV, without major harm [21].
General important points are long-ago described agenda for gut peptides in brain-gut and gut-brain axes, malfunctioning and functioning, based on the evidenced peripheral and central effects on the internal organs and brain lesions [1]. Thereby, neuroleptics, domperidone, and amphetamine effects presented a common periphery-central and centralperiphery link and a common model throughout the occlusion/occlusion-like syndrome of tightly interconnected vascular and multiorgan failure. Corresponding multicausal pathology was in occlusion/occlusion-like syndromes in rats with permanent occlusion of the major vessel(s) peripherally [14][15][16] or centrally [18] and similar noxious procedures [20][21][22][23][24] severely damaging endothelial function. Thereby, the general significance and the beneficial role of the stable gastric pentadecapeptide BPC 157, maintaining epithelium and endothelium integrity is the strong counteracting potential of activation of the collaterals, i.e., azygos vein direct blood flow delivery to the attenuated/eliminated occlusion/occlusion-like syndrome, pleiotropic beneficial effects to reestablish the needed brain-gut and gut-brain axes functioning [1][2][3][4][5][6][7].
Finally, it might be that unable to oppose each other's full harmful effects, combined amphetamine (agonist) and haloperidol (antagonist) together (amphetamine+haloperidol) perpetuated the injurious circle likely within described injury-specific cytoprotection background not specifically related to any receptor disability [1][2][3][4][5][6][7]. However, such a shared class effect may pick up the particular dopamine points that were mutually antagonized, ECG-disturbances (prolonged PQ-intervals, and prolonged QTc-interval (haloperidol) and short QTc-interval (amphetamine) were mutually normalized). These may be special targets, specifically the dopamine system related. On the other hand, the whole perpetuated injurious circle was completely opposed by the stable gastric pentadecapeptide BPC 157 therapy; the BPC 157-related background might be essential.

Animals
Male Albino Wistar rats, 12 weeks old, 200 g body weight, bred in-house at the Animal Pharmacology Facility, School of Medicine, Zagreb, Croatia (registered with the Veterinary Directorate (Reg. No: HR-POK-007)), randomly assigned at 6 rats/group/interval, were used in all experiments. Rats were acclimated for five days and randomly assigned to their respective treatment groups; they were housed in polycarbonate (PC) cages (identified with dates, number of study, group, dose, number, and sex of each animal) at 20-24 • C, relative humidity of 40-70% and noise level 60 dB, illumination 12 h per day (fluorescent lighting), standard good laboratory practice (GLP) diet and fresh water ad libitum. Procedures were in accordance with the standard operating procedures (SOPs) of the Animal Phar- macology
After complete calvariectomy, recordings of brain swelling (before the procedure, after haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, domperidone, amphetamine, and combined amphetamine and haloperidol, after therapy application, and before sacrifice) followed the procedure previously used in our vascular studies, with permanent major vessel occlusion peripheral [14][15][16] and central [18], and similar procedures application [20][21][22][23][24]. Calvariectomy procedure included, medially to the superior temporal lines and temporalis muscle attachments, 6 burr holes drilled in three horizontal lines (just basal from the posterior interocular line (two rostral burr holes); just rostral to the lambdoid suture (and transverse sinuses) on both sides (two basal burr holes); in line between the basal and rostral burr holes (two middle burr holes)).

Superior Sagittal Sinus, Portal, Caval Vein, and Abdominal Aorta Pressure Recording
Recordings followed the procedure used and described in detail in our previous vascular studies with permanent major vessel occlusion peripheral [14][15][16] and central [18], and similar procedure application [20][21][22][23][24] (deeply anesthetized rats, a cannula (BD Neoflon™ Cannula) connected to a pressure transducer (78534C MONITOR/TERMINAL; Hewlett Packard, Palo Alto, CA, USA), inserted into the portal vein, inferior caval vein, and superior sagittal sinus, as well as the abdominal aorta at the level of the bifurcation at 15 min after haloperidol, fluphenazine, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, domperidone, and amphetamine, and combined amphetamine and haloperidol. The superior sagittal sinus anterior part was cannulated using a Braun intravenous cannula, and then, after laparotomy, the pressure in the portal vein, inferior vena cava, and abdominal aorta was recorded.
Accordingly [14][15][16]18,[20][21][22][23][24], superior sagittal sinus pressure of −24 to −27 mm Hg, portal pressure of 3-5 mm Hg similar to that of the inferior vena cava, although with values at least 1 mm Hg higher in the portal vein, and abdominal aorta blood pressure values 100-120 mm Hg at the level of the bifurcation were considered to be normal in healthy rats.

Brain Volume, Heart, and Vessel Volume Presentation
The applied procedure was used in our previous vascular studies [14][15][16]18,[20][21][22][23][24]. Brain volume, vessel volume, and heart volume were proportional to the change in the brain or vessel or heart surface area. The presentation of the brain and peripheral vessels (superior mesenteric vein, inferior caval vein, azygos vein, and abdominal aorta) was recorded in deeply anesthetized rats, with a camera attached to a VMS-004 Discovery Deluxe USB microscope (Veho, Claymont, DE, USA). The border of the brain (or vessels or heart) in the image was marked using ImageJ software, and then the surface area of the brain (or vessels or heart) was measured. This was done with the brain (or vein) images for healthy rats, and then for both the control (saline) group and treated (BPC 157) group of rats at the same intervals after the application and at the time of sacrifice. The arithmetic mean of the surface areas was calculated for both groups. Then, the ratio of these two areas was calculated as ( A con A bpc ), where Acon is the arithmetic mean brain (or veins or heart) area of the control group, and Abpc is the arithmetic mean brain (or veins or heart) area of the treated group. Starting from the square-cube law, Equations (1) and (2), an equation for the change in brain (or veins or heart) volume proportional to the change in brain surface area (or veins, or heart) (6), were derived. In expressions (1)-(5), l is defined as any arbitrary one-dimensional length of the brain (for example, rostro-caudal length of the brain) (or veins or heart), used only for defining the one-dimensional proportion (l 2 /l 1 ) between two observed brains (or veins) and as an inter-factor (and because of that not measured (6)) for deriving final expression (6). The procedure was as follows: (1) (square-cube law), (square-cube law), (from (1), after dividing both sides by A1), (from (3), after taking the square root of both sides), (from (2), after dividing both sides by V1), (after incorporating expression (4) into Equation (5)).
We also assessed the neuronal pathological changes in acquired digital images saved as uncompressed 24-bit RGB TIFF files in the software program AnalySIS (Olympus Soft Imaging System GmbH, Munster, Germany) performing quantitative analysis of neuronal damage in the karyopyknotic areas. The neurons of the cortical cerebral, cerebellar region, hippocampus, and hypothalamus were counted in 10 different high-powered fields (HPF, 400×), and 3 to 5 serial sections of each sample were used to conduct the count as described [96]. The field size was 0.24 µm 2 .
We used four criteria for the estimation of the edema: pale myelin, sieve-like appearance of myelinated areas, dilation of perivascular and pericellular spaces, and vacuolar appearance of the neuropil of gray matter. Edema was graded as heavy, moderate, slight, or no edema (score 0-3) [97].

Statistical Analysis
Statistical analysis was performed by parametric one-way analysis of variance (ANOVA), with the Newman-Keuls post hoc test or the nonparametric Kruskal-Wallis test and, subsequently, the Mann-Whitney U test to compare groups. Values are presented as the mean ± standard deviation (SD) and as the minimum/median/maximum. To compare the frequency difference between groups, the chi-squared test or Fisher's exact test was used. p < 0.05 was considered statistically significant.

Conclusions
In resolving the issue of the brain-gut and gut-brain axes (mal)functioning [1], we revealed as the new practical point, the central-peripheral and peripheral-central link, the occlusion/occlusion-like syndrome shared with dopamine agents. This implied haloperidol, fluphenazine, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, domperidone, amphetamine, and combined amphetamine and haloperidol, and all particularities, consistently reversed by the stable gastric pentadecapeptide BPC 157. There, we start to highlight the significance of a full new topic (activation of collaterals, i.e., azygos vein as a common "bypassing key" for neuroleptic, domperidone, and amphetamine disturbances). Likewise, we initiate the essential matching of these findings with relationships that they are supposed to mimic (i.e., catalepsy, schizophrenia symptoms [28,29]). There is also the matching with the occlusion/occlusion-like syndromes induced by the major vessel(s) occlusion and other similar procedure applications [14][15][16]18,[20][21][22][23][24]. Noteworthy, these congruent findings' full significance remains to be further fully determined. However, these might be all consistently seen as a network of evidence for the physiologic significance of the revealed BPC 157/vascular-system interplay (i.e., BPC 157 was found in situ hybridization and immunostaining studies in humans to be largely distributed in tissues [8,91] and may have additional physiologic regulatory roles [1-10]). This issue was also approached by other reviews [100][101][102]. Based on the alike beneficial effects, similar importance was suggested also for other species (i.e., birds [103] and insects [104,105]). Moreover, there is also a very safe BPC 157 profile (i.e., no adverse effects in clinical trials (ulcerative colitis, phase II), and in toxicological studies, lethal dose (LD1) could be not achieved) (for review see [1][2][3][4][5][6][7][8][9][10]50,51,76,77,91]). This point was recently confirmed in a large study conducted by Xu and collaborators [106].
Together, these findings may be suggestive of the further BPC 157 therapy application.

Data Availability Statement:
The data presented in this study are available on request from the corresponding authors.

Conflicts of Interest:
The authors declare no conflict of interest.