Spinal cord injury cases worldwide are about 50–80 per million population largely affecting males during traffic accidents (Barbiellini Amidei et al., 2022, Sabariego et al., 2023, World Health organization, 2022). This amounts to about 250–500k spinal cord injury cases per year across the Globe. In military personnel spinal cord injury is very common and about 300k service members are affected by spinal cord injury that require lifelong support and care. Unfortunately, spinal cord injury in military population is growing and roughly affects more than 17k service members every year in America (Spinal cord injury, 2023). Thus, novel approaches and expanding our understanding on the pathophysiology of spinal cord injury is highly warranted.

New therapeutic approaches using noel drugs or their delivery through nanoformulations as well understanding the neurochemical basis of spinal cord injury and progression of the disease pathology is highly needed. In this direction, we for the first time showed that nanodelivery of compounds when applied over the traumatized spinal cord are able to thwart blood–spinal cord barrier (BSCB) breakdown, edema formation and cell injury (Sharma et al., 2007). The idea of topical application over the traumatized spinal cord of drugs or antibodies either using conventional approach or their delivery through nanoformulations delay the progression of spinal cord injury induced secondary injury consequences. Thus, if the military personnel injured at the battlefield neuroprotective drugs or agents can be applied immediately over the traumatized cord and then the victims could be transported to the special facility hospitals for proper treatment.

In this series we found that topical application of brain derived neurotrophic factor (BDNF), insulin like growth factor-1, glia cell line derived neurotrophic factor (GDNF) either given alone or in combination are able to thwart spinal cord pathology, edema and spread of BSCB beyond the injury site is significantly attenuated up to 5 h after the initial trauma (Sharma et al., 2003, Sharma, 2007b, Sharma and Sharma, 2012, Sharma et al., 1997, Sharma et al., 1998, Sharma et al., 2000, Sharma, 2007a). This suggests that topical application of neurotrophic factors is able to thwart spinal cord pathology after trauma.

In search of other molecules and drugs or enzymes we applied on the spinal cord injured segments 2–5 min after primary injury to reduce cord pathology at least up to 5 h after initial trauma (Sharma and Sharma, 2008, Sharma and Sharma, 2012a, Sharma and Sharma, 2012b). In this regard, we find monoclonal antibodies to serotonin, dynorphin A (1–17), neuronal nitric oxide synthase (nNOS), tumor necrosis factor-alpha and histamine when applied individually induces marked neuroprotection up to 5 h after injury (Sharma et al., 1995, Sharma et al., 2006, Sharma et al., 1996, Sharma et al., 1997, Sharma et al., 2003, Winkler et al., 1995, Winkler et al., 2000a, Winkler et al., 2002).

We also examined influence of conventional drugs on neuroprotective effects in spinal cord injury up to 5 h period after primary trauma to facilitate patients in transporting for the battlefield to super specialty hospital for further treatment in time. In this regards several conventional drugs and combination of neurotrophic factors prepared commercially for inducing marked neuroprotection until 5 h after spinal cord injury (Menon et al., 2012, Nyberg and Sharma, 2002, Olsson et al., 1995, Sahib et al., 2020, Sharma et al., 1993, Thörnwall et al., 1997, Winkler et al., 1994a, Winkler et al., 2000b, Winkler et al., 1994b). These observations support the idea that serotonin, prostaglandins, opioid peptides, nitric oxide and carbon monoxide participate in spinal cord pathophysiology (Sharma and Westman, 2004, Sharma, 2004a, Sharma, 2005).

Alterations in neurotransmitters in spinal cord injury are also associated with oxidative stress and histamine metabolism (Badenhorst et al., 2005, Bains and Hall, 2012, Hall and Braughler, 1986, Sharma et al., 2006, Sharma et al., 2017). Thus, we have used a potent inhibitor of lipid peroxidation compound H-290/51 in treating spinal cord injury for neuroprotection for at least 5 h after primary lesion (Sharma and Sjöquist, 2002, Sharma et al., 2000, Sharma et al., 2003, Sharma et al., 2006, Sharma et al., 2009, Sharma et al., 2006). Interestingly, when H-290/51 was delivered through TiO2 nanowired technology in CNS injury, superior neuroprotection was achieved as compared to their conventional treatment (Muresanu et al., 2012, Muresanu et al., 2020, Sharma et al., 2009, Sharma et al., 2018, Sharma et al., 2021). Also nanowired delivery of histaminergic drugs induces superior neuroprotection in neurodegenerative diseases (Patnaik et al., 2000, Patnaik et al., 2018, Sharma et al., 1992, Sharma et al., 2017, Sharma et al., 2021, Sharma et al., 2017). These observations suggest that histaminergic receptor modulator drugs are powerful neuroprotective agents in CNS insults and their efficacy may further be enhanced with addition of antioxidant compound H-290/51. Thus, in this investigation, potential role of nanowired delivery of histamine H3 and H4 receptor modulating drugs with H-290/51 in combination was examined during their nanowired delivery in spinal cord injury for an extended period of 24 h after the primary lesion.

Histamine is one of the potential mediators of blood–brain barrier (BBB) permeability and vasogenic brain edema formation (Patnaik et al., 2000, Sharma et al., 1992, Wahl et al., 1988). Histamine is a biogenic amine present in the mast ells and in the neurons distributed throughout the brain and spinal cord (Panula and Nuutinen, 2013, Panula, 2021). The cell bodies of histaminergic neurons are present in tuberomamillary nucleus (TMN) in hypothalamus and from there projections are widely distributed throughout within the central nervous system (CNS) including cerebral cortex, cerebellum, limbic system, posterior pituitary and spinal cord (Haas and Panula, 2003, Panula and Nuutinen, 2013, Panula et al., 1984, Panula et al., 1989, Panula, 2021). Due to widespread distribution of histaminergic neurons in the CNS the amine is involved in several physiological and pathological processes of the CNS (see Panula, 2021).

Involvement of histamine in BBB breakdown and brain edema formation indicates its role in traumatic brain injury (Engel, 1970, Liao et al., 2019, Lozada et al., 2005, Michinaga et al., 2022, Shimada et al., 2012, Unterberg et al., 2004, Valko et al., 2015). Our results are the first to show increase in plasma and brain histamine after a focal cerebral cortical lesion in the rat (Mohanty et al., 1989) that was in line with the findings of increased histamine content in cryogenic lesion in mice (Orr, 1988). Traumatic brain edema is significantly reduced by pretreatment with histamine H2 receptor antagonist cimetidine indicating that histamine H2 receptors play important role in brain edema formation (Mohanty et al., 1989). Based on these lines spinal cord injury was performed in our laboratory using a longitudinal incision of the right dorsal horn over the T10–11 segment resulting in profound disruption of the blood–spinal cord barrier (BSCB) and massive spinal cord edema formation (Olsson et al., 1990, Sharma and Olsson, 1990) not only in the injured segment but the perifocal rostral and caudal segments also showed BSCB disturbances and edema formation (see Sharma, 2005). Since the permeability properties of the BBB and BSCB are quite similar in nature, further experiments were conducted to find a role of histamine in spinal cord injury using histamine receptor antagonists (Sharma, 2004b). Our results show that histamine H2 receptor antagonist cimetidine or ranitidine markedly reduced BSCB, spinal cord blood flow (SCBF) and edema formation following spinal cord injury (Sharma et al., 2006, Sharma et al., 2017).

These observations indicate that histamine plays and important role in spinal cord injury induced BSCB breakdown and edema formation (see Sharma, 2005; Sharma & Olsson, 1990).

Histamine H3 and H4 receptors identified rather recently and several agonists and antagonists ligands are developed for therapeutic use (Kiss and Keserű, 2016, Lim et al., 2005, Panula et al., 2015, Tiligada et al., 2009). Histamine H3 receptors are localized mainly within the CNS whereas; H4 receptors are largely present on hematopoietic cells indicating their neurotransmission and immunomodulatory functions (Panula et al., 2015, Tiligada et al., 2009). The H3 receptors are expressed in neurons in cerebral cortex, hippocampus, nucleus accumbens, amygdala, globus pallidus, striatum and hypothalamus primarily as presynaptic autoreceptor regulating synthesis and release of histamine from histaminergic neurons (Tiligada et al., 2009). In addition, H3 receptors are also co-localized on neurons responsible for other neurotransmitters to keep a balance in physiological situations (Panula et al., 2015). On the other hand, H4 receptors are largely involved in the control of immune cell trafficking and in pro-inflammatory conditions (Tiligada et al., 2009). Thus, ligands affecting H3 and H4 receptors either as antagonists and agonist or inverse agonist are developed for their possible use in neurological and other clinical disorders.

Oxidative stress is one of the key factors after spinal cord injury (Björquist et al., 1996, Chio et al., 2022, Guo et al., 2022, Hall et al., 2010, Hall et al., 2016, Islam et al., 2022). Use of a powerful antioxidant and inhibitor of lipid peroxidation H-290/51 (Ayaz et al., 2022, Westerlund et al., 1996) is able to induce neuroprotection in psychostimulants neurotoxicity and in brain or spinal cord injury (Muresanu et al., 2012, Sharma and Sjöquist, 2002, Sharma et al., 2000, Sharma et al., 2003, Sharma et al., 2006, Sharma et al., 2009, Sharma et al., 2009, Sharma et al., 2018, Sharma et al., 2021, Sharma et al., 2006).

Histaminergic receptors ligands for H3 receptors as well as H2 receptors induce profound antioxidant effects and inhibition of lipid peroxidation (Badenhorst et al., 2005, Dai et al., 2007, Jansen et al., 1998, Kuder et al., 2021, Lambat et al., 2002, Patnaik et al., 2018). This suggests that a combination of histamine receptor ligands with H-290/51 may induce superior neuroprotection in spinal cord injury, a feature not reported earlier. In this direction we used histamine H3 receptor inverse agonist BF-2649 with H3 receptor antagonist and H4 receptor agonist clobenpropit in inducing superior neuroprotection in neurodegenerative disease like Alzheimer’s or Parkinson’s disease (Iida et al., 2022, Schneider, 2019, Sharma et al., 2016, Sharma et al., 2017, Sharma et al., 2016). In these investigations we used TiO2 nanodelivery of histamine H3 and H4 receptor modulators drugs that induce superior neuroprotection in Alzheimer or Parkinson’s diseases. Nanoformulation of drugs are considered to induce superior neuroprotection as compared to their conventions delivery in neurological diseases (Sharma and Sharma, 2012, Sharma and Sharma, 2013, Sharma et al., 2016, Sharma et al., 2016, Sharma et al., 2020, Sharma et al., 2021).

Likewise, when H-290/51 is delivered through nanowired technology, it induces far more superior neuroprotection as compared to its conventional delivery (Muresanu et al., 2012, Muresanu et al., 2020, Sharma et al., 2009, Sharma et al., 2018, Sharma et al., 2021). Thus, it would be interesting to combine nanowired delivery of H-290/51 and histaminergic H3 and H4 receptor modulator agents for superior neuroprotection strategies in spinal cord injury. We have seen previously, that nanowired delivery of cerebrolysin in spinal cord injury or other degenerative diseases indices superior neuroprotection as compared to their conventional delivery (Guide for the Care and Use of Laboratory Animals, 2011, Ozkizilcik et al., 2019, Requejo et al., 2018).