Morpho-Functional Characterisation of the Rat Ventral Caudal Nerve in a Model of Axonal Peripheral Neuropathy

Abstract

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.

Effect of age on metabolomic changes in a model of paclitaxel‐induced peripheral neurotoxicity

“…However, we observed a similar persistence of caudal nerve axonal neuropathy in both the young and adult treated animals at the end of the follow-up period with a slight deterioration over time in NCS as expected in such a relevant axonopathy. 19 We also found a more evident fiber loss in adult treated rats compared to young treated animals in both caudal and sciatic nerves, in agreement with previous studies describing a substantial decrease in the density of unmyelinated and myelinated fibers, particularly in the caudal nerve, with maturation. [20][21][22] When analyzing behavioral tests, we found a statistically significant development of mechanical allodynia in the young PTX-treated animals, and a lower mechanical threshold in the adult PTX-treatedanimals compared to controls.…”

“…In addition, neurophysiological studies showed both caudal and digital nerve axonopathy in the adult PTX‐treated group compared with the young PTX‐treated animals, which presented only caudal nerve axonopathy. However, we observed a similar persistence of caudal nerve axonal neuropathy in both the young and adult treated animals at the end of the follow‐up period with a slight deterioration over time in NCS as expected in such a relevant axonopathy 19 …”

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy‐induced peripheral neurotoxicity: The role of nerve excitability testing

“…NCS (as shown in Figure 4) mirrored information gained via morphological observations of the caudal nerves. In both experiments a length‐dependent axonopathy was demonstrated, far severer in the PTX animals than in OHP animals, with a minor motor involvement only in the PTX cohort, as expected on the basis of literature data 2,5,28,34,37 …”

“…Therefore, it is crucial to have robust preclinical models addressing pathogenetic mechanisms 15 . In this regard in vivo models are pivotal and it is mandatory to use translational methods to promptly transfer data from bench to bedside and vice versa; nerve conduction studies (NCS) are quite a relevant option since they can be similarly performed at a preclinical and clinical level in CIPN 1,3,6,9,17,26,27,34 . However, an even more refined option can lead to deeper investigations on axonal damage mechanisms: nerve excitability testing (NET).…”

“…15 In this regard in vivo models are pivotal and it is mandatory to use translational methods to promptly transfer data from bench to bedside and vice versa; nerve conduction studies (NCS) are quite a relevant option since they can be similarly performed at a preclinical and clinical level in CIPN. 1,3,6,9,17,26,27,34 However, an even more refined option can lead to deeper investigations on axonal damage mechanisms: nerve excitability testing (NET). NET is an elegant approach that enables testing axonal properties; it was first devised in a clinical setting 13,16 and later adapted to animal models.…”