Behavioral, cellular and molecular maladaptations covary with exposure to pyridostigmine bromide in a rat model of gulf war illness pain

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

“…During the 1991 Gulf War, soldiers had the potential to be exposed to all three of these categories of AChEIs: the pesticides chlorpyrifos (CPF) and dichlorvos (DDVP) were regularly and pervasively used for pest control, pyridostigmine bromide (PB) was prescribed to be taken every 8 h as a prophylactic against potential nerve agent exposure, and the demolition of ammunition storage facilities released sarin and cyclosarin nerve agents and potentially exposed veterans to these chemical weapons ( Tuovinen et al, 1999 ; Institute of Medicine (US) Committee on Health Effects Associated with Exposures During the Gulf War, 2000 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; White et al, 2016 ). Exposure to AChEIs has been repeatedly implicated as the potential cause of Gulf War Illness (GWI), a chronic multi-symptom disorder affecting nearly one-third of the veterans that returned from the 1991 conflict, by both epidemiological ( Sullivan et al, 2003 ; Research Advisory Committee on Gulf War Veteran’ Illnesses, 2008 ; Steele et al, 2012 ; Kerr, 2015 ; White et al, 2016 ; Sullivan et al, 2018 ) and preclinical studies ( Henderson et al, 2001 ; Amourette et al, 2009 ; Lamproglou et al, 2009 ; Abdullah et al, 2012 ; Abdullah et al, 2013 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Ojo et al, 2014 ; Nutter et al, 2015 ; O’Callaghan et al, 2015 ; Zakirova et al, 2015 ; Abdullah et al, 2016 ; Cooper et al, 2016 ; Phillips and Deshpande, 2016 ; Pierce et al, 2016 ; Alhasson et al, 2017 ; Emmerich et al, 2017 ; Flunker et al, 2017 ; Locker et al, 2017 ; Shetty et al, 2017 ; Zakirova et al, 2017 ; Ashbrook et al, 2018 ; Carreras et al, 2018 ; Cooper et al, 2018 ; Koo et al, 2018 ; Macht et al, 2018 ; Miller et al, 2018 ; Phillips and Deshpande, 2018 ; Seth et al, 2018 ; Macht et al, 2019 ; Michalovicz et al, 2019 ). Acute exposure to toxic levels of AChEIs, particularly the organophosphate (OP) compounds like the pesticides and nerve agents, has a number of systemic effects (i.e.…”

“…Unfortunately, to our knowledge, there has been no direct evaluation of GWI-related DDVP exposure in animal models, but DDVP exposure has the potential to produce neuroimmune responses such as microglial activation, increased inflammatory cytokine expression and neurodegeneration ( Kaur et al, 2007 ; Binukumar et al, 2011 ). However, several studies have investigated the potential role of CPF exposure in GWI and found significant neurological effects ( Ojo et al, 2014 ; Hernandez et al, 2015 ; Nutter et al, 2015 ; Cooper et al, 2016 , 2018 ; Flunker et al, 2017 ; Locker et al, 2017 ; Miller et al, 2018 ). Among these studies, investigators have demonstrated that repeated exposure to CPF can cause persistent impairment of axonal transport ( Hernandez et al, 2015 ), loss of synaptic integrity and neurogenesis in the hippocampus ( Ojo et al, 2014 ), and decreased pain threshold when combined with PB, PER and DEET ( Nutter et al, 2015 ; Cooper et al, 2018 ; Flunker et al, 2017 ; Cooper et al, 2018 , 2018 ).…”

“…However, several studies have investigated the potential role of CPF exposure in GWI and found significant neurological effects ( Ojo et al, 2014 ; Hernandez et al, 2015 ; Nutter et al, 2015 ; Cooper et al, 2016 , 2018 ; Flunker et al, 2017 ; Locker et al, 2017 ; Miller et al, 2018 ). Among these studies, investigators have demonstrated that repeated exposure to CPF can cause persistent impairment of axonal transport ( Hernandez et al, 2015 ), loss of synaptic integrity and neurogenesis in the hippocampus ( Ojo et al, 2014 ), and decreased pain threshold when combined with PB, PER and DEET ( Nutter et al, 2015 ; Cooper et al, 2018 ; Flunker et al, 2017 ; Cooper et al, 2018 , 2018 ). While these results do not directly support the neuroimmune dysfunction hypothesis of GWI, conditions like neuropathic pain, impaired hippocampal neurogenesis, and axonal transport deficits have been associated with neuroinflammation ( Ellis and Bennett, 2013 ; Walker et al, 2013 ; Errea et al, 2015 ; Valero et al, 2017 ).…”

“…In addition, a significant number of exposure models have been developed that combine PB with other, non-AChEI, GW-relevant chemicals including: permethrin (PER) with or without stress ( Abdullah et al, 2011 ; Zakirova et al, 2015 ; Alhasson et al, 2017 ; Nizamutdinov et al, 2018 ; Seth et al, 2018 ; Joshi et al, 2019 ); PER and DEET with or without stress ( Abou-Donia et al, 1996 ; Abdel-Rahman et al, 2002 ; Abdullah et al, 2012 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Megahed et al, 2015 ; Pierce et al, 2016 ; Shetty et al, 2017 ; Carerras et al, 2018 ; Petrescu et al, 2018 ; Madhu et al, 2019 ); PER and CPF with or without DEET ( Ojo et al, 2014 ; Nutter et al, 2015 ; Cooper et al, 2016 , 2018 ; Flunker et al, 2017 ). The prominence of these mixtures in GWI models, which largely revolve around combined exposures with PER and DEET, stem from a recommendation in the report from the Institute of Medicine (US) Committee to Review the Health Consequences of Service During the Persian Gulf War (1995 ) and an initial study of these chemicals in a hen model ( Abou-Donia et al, 1996 ).…”

“…While some of these models have demonstrated neuroimmune-related effects, these models generally evaluate conditions only when all chemical exposures are combined and, therefore, the results are likely due to the other chemicals employed in these models rather than PB. However, one study presented by Cooper et al (2018) found that inclusion of PB in their combination exposure with permethrin, chlorpyrifos, and DEET was requisite for the development of chronic pain and aberrant nociceptor signaling. Overall, the disparity in positive results between models that more directly investigate the role of PB in GWI and those that use combinations with other chemicals like sarin, PER, and/or CPF further highlights the likelihood that PB had a modulatory effect on the response to these other exposures in the initiation of GWI.…”