INTRODUCTION

The well-known outcomes after prostate cancer surgery are diminished sexual function or erectile ability that constitutes erectile dysfunction (ED) [1, 2]. In Korean adult men, prostate cancer ranks sixth in prevalence, and European study on male aging identified nerve injury-related ED in 14% of cancer surgery patients [2, 3, 4]. Despite the surgeon’s competence, prostate traction during pelvic surgery wounded the cavernous nerve, which regulates parasympathetic, sympathetic, and neurotransmitters during erection [4, 5, 6]. First-line oral ED treatments, phosphodiesterase type 5 inhibitors (PDE5i), prevent the enzymatic breakdown of cyclic guanosine monophosphate (cGMP) and induce smooth muscle relaxation [7]. PDE5i treatment failed in most pelvic surgery patients owing to significant cavernous nerve damage [8].

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Photobiomodulation (PBM) therapy, also referred as low-level-light therapy (LLLT), employs the utilization of noninvasive, non-ionizing light source like lasers, light-emitted diodes (LEDs), or broadband light therapeutic methods to initiate desired therapeutic effects [9]. LEDs are able to irradiate cells without overheating due to their broad spectrum, adjustable wavelengths, amplitudes, phases, and low power consumption [10]. PBM employs low-power LEDs in RED and near-infrared (NIR) spectral range, which correspond to the mitochondrial chromophores that activate photophysical and photochemical reactions for intracellular cellular energy transfer, cellular metabolism, and proliferation, and increase mitochondrial metabolism [11, 12]. PBM has been shown the pain-reducing effects in both human subjects [13] and mice [14], facilitate tissue regeneration in mice [15] and humans [16, 17], enhance nerve regeneration in rats [18, 19, 20], mice [21], and rabbits [22], and promote angiogenesis by inducing endothelial cell proliferation and pro-angiogenesis factors in rats [23]. Despite of positive response and rapid recovery after peripheral nerve injury [20], to the best of our knowledge, no research has evaluated erectile response recovery through PBM following cavernous nerve damage in mice. Our goal was to determine the optimal PBM parameters for a mouse model of cavernous nerve injury (CNI) by analyzing molecular, histological, and erectile function data.

RESULTS

1. PBM device and treatment

Fig. 1 illustrates the conceptual framework of PBM-based therapy for CNI mice model. The PBM device used in this study is a low-light-delivery device that administers NIR and RED light to abdominal area of mice and in in-vitro studies. The LED module board was placed under a colorless custom-nontoxic acrylic cage to allow the animals to ambulate freely during each treatment session, and light was delivered perpendicular to the abdominal area in continuous mode for 30 minutes.

2. PBM therapy improves erectile function by enhancing cavernous angiogenesis in CNI mice

Nerve denervation during crush injury leads to abnormalities of nerve, smooth muscle, and endothelial cells that results in ED [5, 25]. Erectile function was examined two weeks after surgery to see whether or not there was an improvement in erectile function due to post-PBM treatment (Fig. 2A). When comparing the cavernous nerve-crushing group to the sham group, both the maximum and total ICP were lower in the cavernous nerve-crushing group. In contrast, the post-PBM group showed significantly improved erectile function, which reached 90% of that in the sham group. Although improvement of erectile function was observed in the RED and NIR groups, a combination of both treatments showed the best improvement in the PBM-treated group. Cavernous tissue was double-stained with antibodies against phospho-endothelial-nitric-oxide synthase (p-eNOS) and platelet and endothelial cell adhesion molecule-1 (PECAM-1) (Fig. 2D) to visualize endothelial cell expression and neuron-glial antigen-2 (NG-2) and smooth muscle α-actin (α-SMA) levels (Fig. 2E) in smooth muscle and pericytes. The cavernous pericyte and also endothelial cell expression of heat-treated cavernous nerve crushed mice were considerably lower than that of the sham group. In contrast, mice treated with RED, NIR, and a combination of PBM these expressions were preserved remarkably (Fig. 2D, 2E). There were no discernible variations in mean systolic blood pressure and body weight across the experimental groups (Supplement Table 1). These findings suggest that PBM alleviates postoperative ED and contributes to the regeneration of damaged smooth muscle and endothelial cell content in CNI mice.

3. PBM therapy stimulates neurovascular regeneration by reducing axonal degeneration and enhance neuronal regeneration in CNI mice

Using immunofluorescence labeling, βIII-tubulin, nerve growth factor (NGF), neurofilament-1 (NF), and neuronal nitric oxide synthase (nNOS) expression in the cavernous (Fig. 3A) and dorsal nerve bundle (DNB) (Fig. 3B) were determined. Expressions of βIII-tubulin and NGF content in the cavernous tissue, as well as nNOS and NF-positive axonal expression in DNB were significantly reduced in the CNI group treated with heat alone in comparison to the sham group, whereas PBM implementation substantially increased expression in both the DNB and the cavernous. This suggests that neuronal regeneration in CNI mice was affected by all three wavelengths (NIR, RED, and combination) of the PBM light.

To assess axonal regrowth and nerve remyelination, triple-labeled immunofluorescence staining of βIII-tubulin, S100, and myelin basic protein (MBP) was done. βIII-tubulin expression indicated the regeneration of neurofilaments and axons, respectively. S100 indicated Schwann cell migration, whereas MBP indicated myelinated nerve cells. After CNI, in mice treated with heat, image analysis revealed a significant reduction in the βIII-tubulin-positive region as well as axonal enlargement with vacuolization, which indicates axonal degeneration (Supplement Fig. 1). The penile DNB expression in PBM-treated mice demonstrated more favorable outcomes through the expression of βIII-tubulin, S100, and MBP than in the CNI mice, shown by non-disrupted compact round axonal structure (shown by S100).

4. PBM stimulated neurovascular regeneration in CNI mice by elevating neurotrophic factor, proangiogenic, and survival signaling expression levels

Activation of the phosphoinositide 3-kinases (PI3Ks) - Akt pathway is essential for the recruitment of growth factors during axon regeneration in the adult peripheral nervous system [26]. In order to promote neurovascular regeneration, PBM activates AKT phosphorylation, leading to elevated levels of neutrophic proteins; human brain-derived neurotrophic factor (BDNF), and pro angiogenic factors [27]. Consistent with previous reports we found that PBM also significantly upregulated neurotrophic factors (BDNF, neurotrophin-3 [NT-3], and NGF), cell survival signaling (PI3K-Akt signaling), angiogenic factors such as angiopoetin-1 (Ang-1) and vascular endothelial growth factor (VEGF) (Fig. 3C). Taken together, our data imply that PBMs-mediated neurovascular regeneration in CNI mice relies primarily on the VEGF, Ang-1, Akt, PI3K, NT-3, BDNF, and NGF signaling pathways.

5. Stimulation of neural regeneration with PBM treatment in both ex-vivo and in-vitro models

During in-vitro study, DRG and MPG were cultivated and subjected to lipopolysaccharide (LPS) 10 µg/mL to mimic neuroinflammatory conditions post prostatectomy and treated with PBM for 30-minutes for five consecutive days to analyze the impact on neural regeneration. In contrast to the control and PBM-treated animals, the heat group had clearly delineated sprouting in their βIII-tubulin expressions. Significant improvement in neurite outgrowth was observed after the explants were exposed to both RED and NIR; moreover, the most remarkable neurite outgrowth was seen in the combination group (Fig. 4A).

6. PBM treatment induces neuroregeneration by increasing proliferation and reducing apoptosis of PC-12 cells

We examined PC-12 cell proliferation (BrdU incorporation assay) and apoptosis (TUNEL test) conditioned with LPS and treated with PBM to learn how PBM therapy improves nerve regeneration. Lessened proliferation and augmented apoptosis of PC-12 cells after LPS treatment were diminished by PBM treatment with RED, NIR, and RED–NIR combination (Fig. 4B). In order to conduct a more comprehensive investigation into the neuroprotective properties of PBM in the context of neuroinflammation, we subjected PC-12 cells to LPS conditioning and subsequently administered light therapy for five days (Supplement Fig. 2). Following this treatment, we performed neurofilament staining and observed that the LPS group, which was exposed to heat only, exhibited a reduced number of neurite branches and shorter neurite lengths in comparison to the PBM group (Supplement Fig. 2). Collectively, our data suggest that PBM therapy elicits neuronal regeneration via the facilitation of cellular proliferation, suppression of cell death, and alleviation of neuronal damage by encouraging neuronal differentiation and neurite outgrowth.

7. PBM therapy promotes neuronal survival and neurotrophic factor expression in CNI mice, thus inducing neurovascular regeneration

Neurotrophic factors and their pro-peptides promote neuronal development and differentiation to a substantial engagement in neuronal survival and postdamage recovery [28]. We used LPS-treated PC-12 cells to mimic the in vivo neuroinflammatory response and Western blotting to analyze the expression of neurotrophic factors that mediate signal transduction after nerve damage. Neuronal injury activates many signaling pathways, leading to an increase in the synthesis of neuroprotective proteins such BDNF, NT-3, and NGFs, which serve to shield healthy neurons from harm while also stimulating the development and repair of damaged nerves [29]. Phosphorylated PI3K and neurotrophic factors; BDNF, NGF, and NT-3 were all downregulated in LPS-treated PC-12 cells, but upregulated in PBM-irradiated cell groups exposed to either NIR, RED, or a combination of the two (Fig. 4C).

DISCUSSION

The current study we examined the effectiveness of PBM therapy in CNI mice. The positive impact of CNI was observed alongside heightened activation of cell survival signaling pathways (specifically, phosphorylation of Akt, PI3K, and eNOS), increased expression of neurotrophic factors (BDNF, NT-3, and NGF), and enhanced levels of angiogenic factors (VEGF and Ang-1). These effects collectively facilitated the sprouting of neurites in DRG and MPG ultimately leading to neuritogenesis in instances of neuronal damage.

This study may provide the understanding of the impact of PBM therapy aids in the reconstruction of crushed cavernous nerves and the subsequent restoration of its function. Most cases of neuropraxia heal spontaneously over time and repair begins shortly after the injury [30]. Nerve cell loss and degeneration arise from reduced postoperative ATP availability and increased oxygen demand [31, 32]. A non-ionizing light source modulates mitochondrial energy metabolism and accelerates peripheral nerve regeneration in PBM [19, 20, 22, 29, 33, 34, 35]. While both types of PBM wavelengths offer benefits for the regeneration of neurons, our study demonstrated that PBM therapy, whether administered as a single or in combination, effectively repairs damaged cavernous nerves by stimulating the production of neuronal factors, facilitating cell survival signaling, and inhibiting the apoptotic signaling pathway. Furthermore, it was found that the most effectiveness was achieved when visible and NIR-LEDs were combined Supplement Fig. 3 provides a comprehensive overview of the specific processes via which PBM therapy enhances erectile function after CNI. Previous studies have used visible or NIR lasers to achieve positive outcomes in experimental investigations [18, 19, 20, 21, 22, 34, 35, 36]. However, it is worth noting that unlike our experiment, the majority of these studies only employed a single kind of laser and no research has been conducted on the effects of PBM on erectile function after CNI in mice or human. In addition, the investigation of neurogenic variables and survival signaling following PBM therapy constitutes a novel element of this work.

PBM treatment stimulates potential transient in receptor vanilloid-1, 2, and 4 in pericytes to generate Ca2+ influx, which promotes endothelial cell proliferation, blood flow control, angiogenesis, neuroprotection, and neuroregeneration [36, 37, 38]. PBM stimulates Ca2+ to regulate the release of growth factors, such as VEGF, platelet-derived growth factor (PEDF), and BDNF, boosts nitric oxide and ATP production for inhibiting mitochondrial apoptotic processes that are essential for angiogenesis and cell regeneration [39]. We observed groups subjected to PBM had increased expression of intracavernous smooth muscle actin, pericytes, and endothelial cells as compared to the heat group. Correspondingly, the upregulation of neurogenic factors BDNF, NGF and NT-3, alongside VEGF and Ang-1 exhibited a significant rise across all subjects in PBM group contributing to the neurovascular regeneration post nerve injury.

The altered expressions of nNOS and NF in the dorsal penile nerves are crucial diagnostic criteria for CNI damage-induced ED, along with a decrease in ICP and symptoms of corpus cavernosum fibrosis [40, 41]. Our result shown that after PBM therapy, there was an enhancement in the expression levels of neurofilament-positive axons, S100 expression, and MBP in mice with CNI. Moreover, an improvement in erectile function was also seen. Upon exposure to LPS, there was a significant decrease in neurite outgrowth in both MPG and DRG, as well as a reduction in neurite elongation in PC-12 cells but this detrimental effect was ameliorated by PBM treatment.

In this study, we hypothesized that PBM-induced attenuation of apoptosis and stimulation of neuroprotection is correspond to the regulation of PI3K and AKT signaling, and in vitro as well as in vivo. We measured the expressions of p-Akt to determine whether PBM therapy reduced oxidative stress after crushing in the cavernous nerve related to PI3K/Akt pathway. We found that phosphorylated-AKT and PI3K expressions were substantially more expressed in PBM treatment groups in contrast to not exposed group. Similarly, previous research shown PBM therapy may modulate cell proliferation by triggering tyrosine-protein kinase receptors (TPKRs), including c-MET, which in turn activate mitogen-activated protein kinases (MAPKs) and encourages functional recovery which suppresses inflammation by means of PI3K/AKT signaling activation promotes neuronal cell survival and participation in post-injury neuronal differentiation and synaptic function [42, 43]. This evidence suggests that PBM modulates survival, proliferation, and regenerative signaling pathways following cavernous injury in mice. However, this study does not explain the complete set of processes that underpin the molecular and cellular process of PBM therapy-regulated pericyte and endothelial cell interactions.

Our device emits RED light with an intensity of 46.8 mW/cm2 and NIR light with an intensity of 85.3 mW/cm2. Regarding the limitation, the measurement of light penetration, the proportion of light reaching the target tissue depth, was not conducted. Nevertheless, previous research has shown that the successful penetration of the spinal cord in rats was attainable with power densities of 35 mW/cm2 and 16 mW/cm2 [44, 45]. Based on this evidence, we possess a high level of assurance that the power output of the RED and NIR wavelengths used in our investigation was adequately capable of penetrating the cavernous nerve during whole abdominal irradiation. While therapy does lead to notable improvements in both functional and cellular aspects, it is essential to conduct more investigations pertaining to the quantification of light energy with specific wavelengths on targeted tissues.

Procedure to ease prostate obstruction improves patients’ quality of life

Published on Monday, July 27,

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By: Ruth Cummins

When an enlarged prostate led to urination problems, Jasper County resident Raleigh Bogan sought help from specialists at the University of Mississippi Medical Center.

Bogan was diagnosed with benign prostatic hyperplasia in . He said his symptoms had worsened in late , and medications didn’t give him relief.

The U.S. Army veteran saw UMMC’s Dr. Jay Vasani, assistant professor of interventional radiology. Vasani told him about a procedure that is relatively new to UMMC, prostate artery embolization. The procedure is minimally invasive and an alternate to a simple prostatectomy, or complete removal of the prostate gland.

Bogan had the surgery on March 12. Today, “I’m doing much better than when all this took place,” Bogan said.

After age 60, about 50 percent of men have lower urinary tract complications due to an enlarged prostate, Vasani said. That often makes it difficult to urinate, he said.

Nodules in the prostate cause the urethra to be obstructed. Bladder thickening due to the enlarged prostate and straining can prevent the bladder from completely filling, although a patient has the sensation that it is full, Vasani said. “The frequency of urination increases, but you aren’t able to completely empty your bladder,” he said.

It’s common for patients with the obstruction to awaken three or four times a night for trips to the bathroom. “It disturbs your sleep and quality of life,” Vasani said.

The primary treatment for the condition has been medication to relax the prostate. “If you get good relief, you don’t need to do anything else,” Vasani said “But many times, the medications have side effects. This procedure is a good fix and a safe alternative to surgery.”

The physician performs outpatient surgery lasting one to two hours using conscious sedation. A small puncture is made in the patient’s upper thigh or waist, and wires and a small catheter are inserted and guided into the prostatic arteries that supply blood to the prostate.

Blood supply to the prostate gland is blocked, causing the problematic tissue to die and the prostate to shrink. That allows urine to more easily flow.

“If there is no blood supply, the nodules die on their own or become soft,” Vasani said. “The pressure on the urethra decreases.”

Recovery takes three to four hours, and patients generally go home the same day.

There is no significant incision, but instead, a small cut in the skin that is covered post-procedure with a Band-Aid, Vasani said. “For the next five to seven days, the patient might have some pain because the prostate gland is inflamed, but it can be controlled with over-the-counter medications.”

Bogan, who became a truck driver after his military service, said he’s glad he had the procedure. Six weeks after his surgery, he had his catheter removed.

“It took a while for everything to fall into place (after the surgery), but Dr. Vasani would call and check on me to see how I was,” he said. “I’m doing fine.”

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