1. Introduction

Damage and regeneration naturally occur in the peripheral nervous system. If the balance of these two processes is disturbed, for example, by chronic diseases such as diabetes, and nerve regeneration is impaired, nerve damage can lead to peripheral neuropathy [1]. Nerve damage can have a single cause (e.g., traumatic compression as a result of acute crush injury or laceration as a result of transection injury), but in many cases (and almost always in the chronic course), it is a combination of reasons, such as laceration, traction, vibration, compression, ischemia, inflammation, alcoholism, metabolic (diabetes) or toxic noxae (chemotherapy), surgery, genetic causes, and deficiency in neurotropic B vitamins [1-6]. However, nerves are amazingly regenerative, and regeneration is even possible until approximately 50% of the fibers within a nerve (considered the “point of no return”) are damaged [1]. When a peripheral nerve is centrally injured, the surrounding nonnerve cells initiate the so-called Wallerian degeneration (Figure 1). In this process, the degradation of axon parts (fragmentation) is regarded as a key event that already occurs within one to a few days after the injury. Subsequently, at the site of injury, macrophages are recruited to carry away myelin and dead cells, and the distal stump degenerates. Furthermore, the nonnerve cell responses promote an environment that supports the regeneration of axons over the following months [7, 8]. It has been suggested that certain B vitamins support this nerve regeneration process (Figure 1). In particular, the vitamins B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) are mentioned in this context. Those are also called “neurotropic” vitamins because of their important functions in the nervous system [9]. Although it is not fully understood how they support the process, numerous animal studies provided evidence for the effect at the histological or molecular level in recent decades. Due to demographic trends, neurodegenerative diseases such as peripheral neuropathy are becoming increasingly important [10] and so will possible treatments.

This is clearly illustrated by diabetes mellitus, which according to the International Diabetes Federation currently affects 463 million people worldwide. Neuropathy is one of the most frequent late complications of this disease [11, 12]. The degeneration process of the nerves does not start with manifestation of diabetes mellitus, but already with impaired glucose tolerance [13]. By the time clinical symptoms of diabetic neuropathy appear, significant and irreversible nerve loss has often already occurred (Figure 1, “point of no return”) [11-13]. It can be speculated that by the time a reduction in nerve conduction velocity of myelinated Aδ nerve fibers is diagnosed, neuropathy has already existed progressively for years, and treatment comes too late. In contrast, the diagnostic method of confocal microscopy of the eye’s cornea, which has been increasingly used in recent years, allows noninvasive detection of changes in the thin C nerve fibers [14-18]. Until now, peripheral nerve fiber density could only be detected invasively by skin punch and subsequent immunofluorescence staining [19]. Independent studies have shown that the loss of skin innervation in diabetic polyneuropathy is preceded by a significant reduction in the nerves of the subepithelial plexus of the cornea [20, 21]. Thus, therapeutic concepts must also be readdressed from the perspective of improved diagnostics. The authors from a double-blind, randomized, controlled study concluded that neurotropic B vitamins represent a starting point in the treatment of diabetic polyneuropathy [22]. In addition to a benefit in the patients’ subjective paresthesias, an improvement was also observed in objectively assessable parameters, such as a decrease in the vibration perception threshold at the second metacarpal and metatarsal bones and an increase in conduction velocity in the peroneal nerve [22]. Other human studies [23-27] and animal experiments [28-30] confirmed the benefit of continuous administration of vitamins B1, B6, and B12 with respect to diabetic neuropathy.

However, to date, there is no recent review article available focusing explicitly on the nerve-regenerating function of B vitamins. Therefore, systematic literature searches were performed to compile the actual evidence from animal studies, provide a current update on this topic for the individual vitamins B1, B6 ,and B12 as well as their combination, and try to derive biochemical explanations.