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

TL;DR

This study explores combining DMT and a surgical technique to protect neurons after spinal injuries in rats, showing promising results.

Contribution

The novel combinatorial therapy of DMT and VRR is shown to enhance neuroprotection after spinal root avulsion.

Findings

DMT at 1 mg/kg significantly enhanced motoneuron survival and reduced glial reactivity.

Combining DMT with VRR further improved synaptic preservation and upregulated neurotrophic factors like GDNF.

The combined therapy showed synergistic effects in protecting neurons after spinal injuries.

Abstract

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.

The ventral root avulsion (VRA) model provides an excellent experimental paradigm for studying injuries at the Central/Peripheral Nervous Systems (CNS/PNS) interface. By physically disconnecting motoneurons (MNs) from the spinal cord surface, VRA induces profound cellular, molecular, and functional deficits with limited spontaneous recovery. Given the complex pathophysiology underlying this injury, combined therapeutic strategies targeting multiple mechanisms simultaneously hold considerable promise. Here, we hypothesized that N, N dimethyltryptamine (DMT) and ventral root reimplantation (VRR) administered either as monotherapies but especially in combination could ameliorate degenerative changes and improve outcomes following VRA.

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