Central delivery of iodine-125–labeled cetuximab, etanercept and anakinra after perispinal injection in rats: possible implications for treating Alzheimer’s disease

During the past few years, there has been an increase in the use of targeted therapies for different kinds of inflammatory disorders. Most of these drugs, including the tumor necrosis factor α (TNF-α) inhibitor etanercept, have a high molecular weight, which prohibits them from passing the blood–brain barrier (BBB). This is no problem when treating diseases such as rheumatoid arthritis, but it becomes an obstacle when the brain is the primary focus of inflammation. The latter is presumed to be the case in brain injury in Alzheimer’s disease (AD). It is suspected that inflammation, as a consequence of amyloid deposition, plays an important role in the cognitive decline in AD [1, 2] and that the intensity of this inflammatory reaction influences the speed of cognitive decline in individual patients [3].

TNF-α is a proinflammatory cytokine known for its activity in several disease conditions [4]. It plays an important role in immune-to-brain communication [5], and increased TNF-α is associated with rapid neurocognitive decline [6] and neuropsychiatric symptoms [7] in AD. The effect of peripheral inhibition of TNF-α in AD was assessed recently in a trial evaluating the effect of etanercept and placebo in 41 patients with AD [8]. Although the drug was well tolerated, there were no significant effects on cognitive function and behavior. However, earlier uncontrolled studies by Tobininick et al, claim benefit from perispinal administration of etanercept in AD [9, 10] and post-stroke patients [11]. If true, these results, which were heavily criticized by Whitlock [12], would open up potential new treatment avenues.

The first question to be asked is whether there is a causal relationship between increased TNF-α activity and cognitive decline in AD. As mentioned above, the role of inflammation in AD has not been fully elucidated. Therefore, TNF-α inhibition as a strategy in this category of patients is questionable. A recent phase II study using peripheral etanercept administration in patients with AD was ineffective [8]. Still, this lack of an effect could have been caused by insufficient inhibition of TNF-α in the central nervous system (CNS) after peripheral administration. This leads to the second question, which is; Does perispinal administration of drugs with a high molecular weight lead to adequate concentrations in the brain? Etanercept does not cross the BBB after peripheral administration, because of its high molecular weight (51 kDa). Tobinick searched for a method to bypass the BBB without having to use more harmful methods of administering drugs and relied on the vertebral venous system (VVS) to accomplish this [9].

In humans, the musculature and the (sub)cutaneous tissues of the back and neck are drained by the external vertebral venous plexus (EVVP) [13, 14]. The EVVP connects with the internal vertebral venous plexus, and both plexuses connect with the basivertebral veins. These three venous entities represent the VVS, also known as the Batson venous plexus, which is thought to be valveless and forms a separate and discrete venous network paralleling, joining, and at the same time bypassing, the longitudinal veins of the thoracoabdominal cavity. The VVS also connects with the intracranial basilar venous plexus and the intracranial dural sinuses [15]. In nonhuman primates, Batson injected radiopaque material into the deep dorsal vein of the penis and demonstrated the existence of a connection between the pelvic venous plexus with the VVS. He also showed that the contrast medium can be redirected into the intracranial venous sinuses after compression (and subsequent temporary obstruction of the inferior vena cava) of the abdomen [13]. In his study, he found an explanation for the observation that metastases of retroperitoneal cancers in humans tend to preferentially distribute to the vertebral skeleton and spinal epidural space and via the cranial sinuses into the brain. Based on these findings and assumptions, Tobinick designed his concept for drug delivery into the brain [9]. He assumed that, after injection into the perispinal soft tissues and subsequently placing the patient in the Trendelenburg position, the retrograde flow within the VVS would result in the delivery of the medication through the cranial veins into the brain. Tobinick et al. have performed and published only one single experiment in rats, visualizing the intracranial distribution of etanercept labeled with the positron emitter Cu-64 [16], and speculate about the mechanism without providing further proof [17]. Positron emission tomography studies in healthy controls or patients have not been performed to date.

In this brief article, the methods published by Tobinick were explored by injecting drugs with a large molecular weight into the cervical perispinal region of Sprague–Dawley rats. As this technique is claimed to be a safe and effective way to administer drugs to the CNS, it could provide a new treatment option for patients with AD.