Combined Neuroprotective Effects of N,N‐Dimethyltryptamine and Ventral Root Reimplantation Following Spinal Root Avulsion in Rats

Currently, no effective treatment exists for injuries at the interface between the CNS/PNS, largely due to their complex pathophysiology and the limited efficacy of single-target therapies. To address this challenge, we investigated a novel combinatorial therapeutic strategy integrating surgical VRR with fibrin sealant biopolymer (FSB) and DMT in a rat model of ventral root avulsion VRA. DMT was extracted from Mimosa tenuiflora roots and structurally characterized using standard analytical methods. Adult female Lewis rats underwent unilateral L4-L6 VRA and received daily DMT treatment (1, 2.5, or 5 mg/kg; i.p) for 2 weeks to determine the optimal therapeutic dose. Subsequently, the identified optimal DMT dose was combined with VRR, and animals were evaluated 2 weeks post-injury. Outcome measures encompassed quantitative assessments of neuronal survival, glial reactivity, synaptic preservation, and differential gene expression of neurotrophic factors (GDNF, FGF-2, VGF-A) and anti-apoptotic genes (Bcl-2, Bcl-XL). Extracted DMT met all structural and analytical criteria for experimental use. Proximal axotomy led to substantial MN loss (78%), accompanied by pronounced glial reactivity and synaptic detachment. DMT at 1 mg/kg yielded the strongest neuroprotective profile, significantly enhancing MN survival, reducing glial reactivity, and preserving pre-synaptic boutons. Notably, these effects were further potentiated when DMT treatment was combined with VRR. Moreover, the combined VRR + DMT therapy significantly upregulated GDNF expression, indicating a synergistic effect on neurotrophic support. Overall, our findings suggest that DMT is a promising neuroprotective agent for treating MN degeneration following CNS/PNS interface injuries, particularly when integrated into a combinatorial therapeutic strategy.