Neural regeneration after spinal cord injury treatment by lavandula angustifolia and human umbilical mesanchymal stem cell transplantation

Spinal cord injury (SCI) is one of the most common causes of paralysis worldwide because the loss of neurons and axons causes permanent neurological deficits which could have influences on quality of life of patients, their family, and society. The complex pathophysiology of SCI, especially the secondary injury cascade, blocks complete recovery after SCI (Dumont et al., 2001). The severity of spinal cord injury depends on the width, spinal level, and extent of the injury. The primary trauma is initial tissue disruption, followed by the initiation of a series of secondary cellular processes that can lead to long-term functional spinal deficits. Because spinal cord injury is associated with increased oxidative stress and induction of inflammatory genes at the site of the injury and in the adjacent regions, neuroprotective agents could be effective to diminish the injury after SCI-hence, therapeutic strategies for spinal cord injury include both neuroprotective and neurotrophic techniques. Acute neuroprotection could inhibit functional damage of neurons after injury and preserve behavioral output. Additionally, decreasing excitotoxicity by reduction in production of nitric oxide (NO), apoptosis, and inflammation could be a main cellular strategy to alleviate injury (Satake et al., 2000; Schumacher et al., 2000). It has been shown that the more antioxidant protection, the better the result of SCI improvement. On the other hand, it has been demonstrated that increased oxidative stress can lead to direct DNA damage, which leads to damaged secondary processes, such as an impaired activity of membrane enzymes. Therefore, it appears that inhibiting the progression of secondary injury to spinal cord neurons is one of the most effective therapeutic strategies in limiting tissue injury of an injured spinal cord (Dumont et al., 2002). In the past ten years, the first cell therapies (ProCord, OEGs, Schwann cells) have started using engineered biomolecules and antibodies. New trials of neuroprotection are underway and several thousand SCI patients have received a variety of cell therapies, bone marrow stromal cells (BMSCs), and cord blood. The rate of progress has been remarkable (Richard et al., 2002), but until today there are no demonstrated treatments for spinal cord injury (Yamaji et al., 2008). Thus, the best course of action is to decrease inflammation and oxidative stress around the damaged neurons and to increase neuroprotective agents. Therefore, we selected two important tenets to choose the best treatments after an assessment of efficacy in order to reach the best result: good accessibility of selected treatments and that the selected treatments should be affordable. Our two selected treatments were lavender, or Lavandula angustifolia (L. angustifolia) and human umbilical mesenchymal stem cells (HUMSCs) derived from umbilical cord Wharton’s jelly. HUMSCs and L. angustifolia are very accessible in Iran and are inexpensive. L. angustifolia is a neuroprotective agent which has diverse therapeutic effects on nervous system disorders (Yaghoobi et al., 2016). HUMSCs play a important role as a neuroregenerative source, and also could have a neuroprotective role. The umbilical cord is a waste product in Iran, so converting a waste product into a valuable neuroregenerative drug could be beneficial. On the other hand, because stem cell therapy has not been as successful as expected yet (Richard et al. , 2002), we need a safe and accessible agent to promote neural regeneration in SCI patients and to potentiate the HUMSCs; for this reason we selected L. angustifolia to potentiate the HUMSCs transplantation results for neural regeneration. It has been shown that systemic delivery of mesenchymal stem cells (MSCs) have therapeutic benefits in a number of experimental treatments for central nervous system disorders. These cells are multipotent stem cells present in adults, and when cultured they have the ability to differentiate into a variety of lineages, including neurons and glial cells. Moreover, the systemic injection of MSCs prepared from adult bone marrow has therapeutic benefits after cerebral artery occlusion (Dumont et al., 2001). BMSCs ares a reliable source of producing neural-like cells after SCI and are more similar to neural stem cells (Yamaji et al., 2008). HUMSCs from Wharton’s jelly are a low-cost source of stem cells that can be easily obtained and propagated in culture without invasive medical procedures or ethical issues (Yaghoobi et al., 2016), possess stem cell properties, are immunotolerable (Yaghoobi et al., 2016), and can be induced to form other cell lineages, such as neurons and glial cells (Mitchell et al., 2003). The initial observation of our studies was that a single injection of HUMSCs 48 hours after trauma markedly decreased inflammation in the injured region and improved the locomotion of rats. Although extract of L. angustifolia potentiated the effects of HUMSCs transplantation, on its own it was found to significantly decrease damage and inflammation as well as improve locomotion. In our studies, we found that the effective dose of L. angustifolia hydro-alcoholic extract was 400 mg/kg and the lethal dose of L. angustifolia hydro-alcoholic extract was 800 mg/kg. Our studies showed that L. angustifolia significantly improved behavioral results; such as the Basso, Beattie, and Bresnahan (BBB), sensory test, and electrophysiological evaluation results. L. angustifolia also increased the number of the ventral horn motor neurons and decreased the number of astrocytes and therefore decreased astrogliosis. The result of intraspinal transplantation of HUMSCs to the injured spinal cord was similar to L. angustifolia, and when we used a combination of L. angustifolia and HUMSCs, the results were stronger. The results of behavioral tests significantly increased improvement; for example, the blood-brain barrier, sensory test, and electrophysiological evaluation results were improved in comparison with either single treatment (Kaka et al., 2016; Yaghoobi et al., 2016). The increase of the number of ventral horn motor neurons and decrease of the number of astrocytes were better than either single treatment. In our study, we strongly demonstrated that extract of L. angustifolia could have neuroprotective effects (Yaghoobi et al., 2016) to diminish cavity area of gray and white matter in injured spinal cord (Kaka et al., 2016; Yaghoobi et al., 2016) (Figure 1). These findings may have significant implications for elucidation of the cellular and molecular mechanisms involved in L. angustifolia and HUMSCs neuroprotection and may constitute as an attractive therapeutic target in injured area after SCI.