Pentosan Polysulfate: A Pleiotropic, Antiarthritic Compound

Pentosan polysulfate (PPS) is a semi-synthetic, sulfated polysaccharide from the wood of the beech plant, Fagus sylvatica. Daily oral or weekly subcutaneous administration of PPS has pleiotropic effects on health, including inhibiting the degradation of and increasing the synthesis of joint tissue. As its primary side effect, maculopathy, is seen mostly after many years of use, intermittent or 1-2 years of PPS use may be an attractive option for athletes.


This blog post is a companion piece to a YouTube video, which you can access here. In this post, we will survey papers on PPS’s effects on health, paying particular attention to its effects on joints integrity.


Metabolism


1. PPS has an average molecular weight of 4000-6000 Da, similar to that of low molecular weight heparin[1].

2. Oral PPS, brand name Elmiron, is an FDA-approved treatment for interstitial cystitis (IC).

a. Pharmacokinetics in humans resembles those in rodents. Oral bioavailability is less than 1% with the majority of PPS being excreted, unchanged, in feces (84%). Metabolites in urine (6%) were of a lower molecular weight and desulfated, indicating PPS was metabolized by depolymerization and desulfation[2].

b. Oral PPS is of different molecular weights. This in vivo study of PPS pharmacokinetics in rabbits indicates that urinary recovery of PPS is almost entirely composed of low molecular weight PPS when it is orally administered and less so when it is administered IV[3].

3. Injectable PPS, brand name SP54[4].

a. Injectable heparin, low molecular weight heparin, and SP54 were trialed in humans. Molecular weight was inversely associated with absorption during subcutaneous injection[5].


The Brain


1. PPS, as well as the low molecular weight version of heparin named dalteparin, attenuates hippocampal neuronal damage due to ischemia/reperfusion when administered post-operation, suggesting that PPS may be neuroprotective for ischemic stroke[6].

2. PPS has anti-prion effects in vitro and in vivo[7], likely modulated by PPS’s interaction with heparin binding sites on prion proteins[8].

3. PPS has been shown to reduce the size and number of beta amyloid plaque aggregates, and to protect the blood brain barrier integrity, in a rodent model of Alzheimer’s disease[9].


Iron and Blood


1. Like commercial heparins, PPS is an inhibitor of hepcidin (a central regular of iron homeostasis) synthesis[10].

a. It has 1/15th the anticoagulant activity of heparin.

2. PPS dose-dependently increases the partial thromboplastin time (PTT) in horses[11].


Bladder Ailments


1. Interstitial cystitis (IC) is a disease believed to be caused by a weak bladder epithelium, resulting in diffusion of components of urine across the bladder wall, producing an autoimmune reaction. It is more frequently observed in women and characterized by pelvic pain and urgent, frequent urination.

a. It is effectively treated with oral glycosaminoglycan (PPS) as an add on therapy[12].

b. Fascinatingly, IV infusions of 6000 mg NAC per infusion cycle resolved IC in a case report, likely via a reduction in inflammatory cytokine activity (all reduced, except for IL-6, which increased, inexplicably)[13].


Cardiovascular Disease


1. In Watanabe heritable hyperlipidemic (WHHL) rabbits fed an atherogenic diet who developed severe atherosclerosis, one month of treatment with oral PPS “retards” the progression of atherosclerosis[14].

2. In rodents with heart pressure overload due to aortic banding, PPS treatment’s near 80% inhibition of the aggrecan ADAMTS4 protects systolic function, indicating PPS may be an effective therapy for heart failure[15].

a. Interestingly, ADAMTS2 appears to play a causal role in the development of cardiomegaly due to pressure overloads[16], while in the brain, ADAMTS4 may be necessary for the myelination of oligodendrocytes[17].


Diabetes


1. PPS has been shown to attenuate inflammation in aging diabetic mice.

a. This in vitro study of high glucose treated renal cells found that PPS inhibited apoptosis and inflammation via blocking p38 MAPK activation, inhibiting NF-kB activation, and reducing the synthesis of TNF-a, IL-1B, and IL-6[18].


Cancers


1. In vitro and in vivo rodent models, PPS treatment inhibits paracrine effects of heparin-binding growth factors (HBGFs, which proliferate endothelial cells and produce local angiogenesis) released from tumor cells[19].

2. In vivo phase I human trials have yet to show a prominent anti-tumor effect[20].

a. They have revealed GI bleeding and toxicity from oral PPS treatment in volunteers with advanced malignancies[21]. In this study, 3 patients with sarcomas had their disease progression halt until 1-3 months after PPS cessation, whereby the malignancy began to progress again.

i. Chronic oral dosing also produced rectal ulcers, which were not seen in subcutaneous and intravascular studies.

1. The rectal ulcers were likely due to PPS mostly not being absorbed in the GI tract and accumulating in the distal rectum prior to evacuation, or due to PPS binding to basic fibroblast growth factor (bFGF) and thereby depleting local GI tissue of a protectant.

a. A later study confirmed FGF-2’s role in PPS induced structural changes in intestinal vessels, producing lethal intestinal hemorrhages in mice[22].

ii. The authors suggest intermittent dosing may be more effective because it allows the washing out of bFGF, preventing its upregulation.


Kidney Disease


1. In a rodent model of diabetic nephropathy (DN), oral PPS treatment in elderly rodents preserved kidney function, reduced albuminuria, inhibited pro-inflammatory gene expression[23].

2. PPS may prevent the recurrence of kidney stones by decreasing liver glycollate oxidase (GAO) activity[24].

3. In a rodent model of ischemia/reperfusion-dependent acute kidney injury (AKI), long-term PPS treatment attenuated AKI in diabetic rodents while a single high-dose parenteral administration of PPS prior to revascularization may be protective even in non-diabetic rodents[25].

4. In patients with chronic kidney disease (CKD), 3 months of PPS treatment reduced the expression of pro-inflammatory cytokines TNF-a and IL-18, reduced proteinuria, and improved eGFR. It also lowered total cholesterol levels[26].

5. In rodents, PPS is kidney-protective in the 5/6 nephrectomy model by attenuating glomerular hypertension and suppressing inflammation[27].

6. In rodents, PPS treatment confers kidney protection from sodium-induced hypertension. The protective effect is associated with increased P2X1 receptor reactivity[28].


Immune Function