Hello! I am an independent researcher at Uppsala University/Karolinsa Institutet, Sweden and working in the field of neuro-immunology by focusing to understand tendon healing, inflammation and pain mechanism. In addition, I am also trying to understand chronic oral inflammatory diseases (e.g., periodontitis) and systematic diseases including rheumatoid arthritis and diabetes by understanding their molecular mechanisms.
Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular ... more Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular in allergic conditions. There is also limited evidence implicating MCs in diabetes, raising the possibility that MC function may be influenced by alterations in glucose levels. However, it is not known whether MCs are directly affected by elevated glucose concentrations. Moreover, it is not known which glucose transporters that are expressed by MCs, and whether MCs are dependent on glucose transporters for activation. Here we addressed these issues. We show that MCs express high levels of both glucose transporter 1 (GLUT1/Slc2A1) and GLUT3 (Slc2A3). Further, we show that the inhibition of either GLUT1 or GLUT3 dampens both MC degranulation and cytokine induction in response to IgE receptor crosslinking, and that combined GLUT1 and GLUT3 inhibition causes an even more pronounced inhibition of these parameters. In contrast, the inhibition of GLUT1 or GLUT3, or combined GLUT1 and GLUT3 inhibition, had less impact on the ability of the MCs to respond to activation via compound 48/80. Elevated glucose concentrations did not affect MC viability, and had no stimulatory effect on MC responses to either IgE receptor crosslinking or compound 48/80. Altogether, these findings reveal that MCs are strongly dependent on glucose transport via GLUT1 and/or GLUT3 for optimal responses towards IgE-mediated activation, whereas MC functionality is minimally affected by elevated glucose levels. Based on these findings, antagonists of GLUT1 and GLUT3 may be considered for therapeutic intervention in allergic conditions.
Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between... more Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.
Background: Both acute and chronic Achilles tendon ruptures are affected by alterations in the ex... more Background: Both acute and chronic Achilles tendon ruptures are affected by alterations in the extracellular matrix during the healing process of the tendon. Yet, these alterations in gene expression patterns are not well characterized. Purpose: To characterize temporal and spatial differences in gene expression patterns after an Achilles tendon rupture and to evaluate if cells from chronic Achilles tendon ruptures have the same ability to form new tendon tissue (tendon constructs) as healthy tendon cells. Study Design: Controlled laboratory study. Methods: A total of 35 patients with surgically treated Achilles tendon ruptures were included in the study and divided into 3 groups: acute (\4 weeks), short-term chronic (1-6 months), and long-term chronic (.6 months). Biopsy specimens were collected during surgical repair and were used to analyze the gene expression within the different groups and to compare mRNA levels in the proximal and distal tendon ends. A complementary in vitro experiment was performed to evaluate if cells from chronic Achilles tendon ruptures can form tendon constructs. Results: The mRNA levels for COL1A1 and COL3A1 were significantly higher in the short-term chronic group compared with the acute group (P \ .05). Both MMP-1 and MMP-13 had the highest mRNA levels in the acute group (P \ .01) compared with the long-term chronic group, while MMP-2 had the highest mRNA level in the short-term chronic group. Significant differences between the proximal and distal tendon ends were only detected for the monocyte and macrophage marker CD163 (P \ .05), which was more expressed proximally. Cells extracted from chronic Achilles tendon ruptures displayed a similar ability and effectiveness to form tendon constructs as healthy tendon cells. Conclusion: A high collagenase gene activity after an Achilles tendon rupture indicated possible rapid matrix degradation in the acute phase. Chronic ruptures appeared to initiate the healing process even before treatment, indicated by the higher expression of collagen in the short-term chronic group. Cells from chronic Achilles tendon ruptures also displayed an ability to form new tendon tissue in vitro. Clinical Relevance: The study shows a rapid increase in collagenase gene expression, which could lead to matrix degradation that continues for months after an Achilles tendon rupture.
Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdo... more Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdown of gingival tissue, the periodontal ligament, and alveolar bone, leading ultimately to tooth loss. We previously reported the pleckstrin gene (PLEK) to be highly upregulated in gingival tissue of patients with CP and the only gene concurrently upregulated in other inflammatory diseases including rheumatoid arthritis and cardiovascular diseases. Using saliva from 169 individuals diagnosed with CP and healthy controls, we investigated whether pleckstrin could serve as a novel biomarker of periodontitis. Additionally, we explored signal pathways involved in the regulation of PLEK using human gingival fibroblasts (HGFs). Pleckstrin levels were significantly higher (p < 0.001) in the saliva samples of patients with CP compared to controls and closely associated with CP severity. Immunohistochemical analysis revealed the expression of pleckstrin in inflammatory cells and gingival fibroblasts of CP patients. To explore the signal pathways involved in pleckstrin regulation, we stimulated HGFs with either interleukin-1β (IL-1β) or lipopolysaccharides (LPS) alone, or in combination with inhibitors targeting c-Jun N-terminal kinase, tyrosine kinase, protein kinase C, or p38 MAP kinase. Results showed that IL-1β and LPS significantly increased PLEK mRNA and pleckstrin protein levels. VX-745, the p38 MAP kinase inhibitor significantly decreased IL-1β- and LPS-induced pleckstrin levels at both the mRNA and the protein level. Together, these findings show that pleckstrin could serve as a salivary biomarker for the chronic inflammatory disease periodontitis and a regulator of inflammation via the p38 MAP kinase pathway.
Mast cells are emerging as players in the communication between peripheral nerve endings and cell... more Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon h... more Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon homeostasis/pain after tissue damage is crucial in developing novel therapeutics for human tendon disorders. The inflammatory mechanisms that are operative in response to tendon injury are not fully understood, but it has been suggested that inflammation occurring in response to nerve signaling, i.e., neurogenic inflammation, has a pathogenic role. The mechanisms driving such neurogenic inflammation are presently not clear. However, it has recently been demonstrated that mast cells present within the injured tendon can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling and thereby modulate neurogenic inflammation following tissue injury. In this review, we discuss the role of mast cells in the communication with peripheral nerves, and their emerging role in tendon healing and inflammation after injury.
Objectives Management of chronic tendon pain is difficult and controversial. This is due to poor ... more Objectives Management of chronic tendon pain is difficult and controversial. This is due to poor knowledge of the underlying pathophysiology of chronic tendon pain, priorly known as tendinitis but now termed tendinopathy. The objective of this topical review was to synthesize evolving information of mechanisms in tendon pain, using a comprehensive search of the available literature on this topic. Content This review found no correlations between tendon degeneration, collagen separation or neovascularization and chronic tendon pain. The synthesis demonstrated that chronic tendon pain, however, is characterized by excessive nerve sprouting with ingrowth in the tendon proper, which corresponds to alterations oberserved also in other connective tissues of chronic pain conditions. Healthy, painfree tendons are devoid of nerve fibers in the tendon proper, while innervation is confined to tendon surrounding structures, such as sheaths. Chronic painful tendons exhibit elevated amounts of pa...
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's d... more Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by motor symptoms, such as rigidity, resting tremor, and bradykinesia, mainly caused by the progressive death of midbrain dopaminergic neurons in the nigrostriatal cells. Accumulating evidence indicates that PD is also accompanied by a wide range (50% of PD patients) of non-motor symptoms (NMS) including sleep disturbances, and neuropsychiatric and cognitive deficits. These symptoms often appear in the early, pre-motor stage of the disease, when the dopaminergic degeneration is still partial. The pathophysiology of NMS in PD is still a matter of debate and, as a consequence, an efficient therapy has not yet been identified. For these reasons, the preclinical research on PD is nowadays particularly focused on the development of new animal models for the study of the biological correlates of these symptoms. To investigate the NMS of PD, we produced a mouse model characterized by partial depletion of the nigrostriatal dopaminergic system. For this purpose, we subjected C57BL/6J mice to a bilateral injection of 6-hydroxy dopamine into the dorsal striatum. The efficacy of the surgery was verified by western blotting quantification of the remaining tyrosine hydroxylase in the striatum of mice. Nonetheless, the lesioned and control mice were tested with behavioral tasks commonly used to evaluate depression and anxiety in mice. We showed that the lesion produces in mice an anxiety-and depression-like phenotype. Moreover, we found that these deficits were insensitive to L-DOPA, the most common drug used to treat motor symptoms in PD patients. Conversely, both anxiety and depression were reverted in our mouse model, by the administration of the selective dopaminergic D2 receptor agonist Pramipexole. Interestingly, we also found that Citalopram and Reboxetine, serotonin and noradrenaline transporter inhibitors respectively, fully restored the behavior of lesioned mice. Importantly, these data are in line with clinical observations that report a therapeutic effect of these drugs on anxiety and depression in PD patients.
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA, 2017
Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles te... more Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing. One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were l...
Whether neuromediator displays a pathway of signaling to mast cells has been mysterious until rec... more Whether neuromediator displays a pathway of signaling to mast cells has been mysterious until recently when the expression of glutamate receptors on mast cells was established by both in-vivo and in-vitro studies. We recently demonstrated that exposure of mouse mast cells to neuromediator (e.g., glutamate) activates a broad range of glutamate receptors, of both ionotropic and metabotropic types. Our earlier studies also indicate that mouse mast cells may respond to glutamate receptor antagonists. It was further observed that the exposure of mast cells to glutamate resulted in an increased level of pro-inflammatory cytokines/chemokines and transcriptional response, introducing the concept of a glutamate-glutamate receptor axis in mast cells, which can contribute to neuroinflammation and pain regulation in peripheral soft tissues (e.g., tendon). Different neuromediator including glutamate, Substance P, and calcitonin generelated peptide (CGRP) have the excitatory response both in the peripheral and central nervous system and have been implicated in various diseases including pain, neurogenic inflammation, and cancer. Optimal neuromediators response is crucial for the body but in excess, however, it is harmful and causes many disorders including neuronal death through a massive calcium influx via its specific (e.g., glutamate via ionotropic and/or metabotropic) receptors. The glutamate-glutamate receptor axis in mast cells is exclusive. However, mast cells are emerging players in the communication between peripheral nerve endings and the immune system. It is not so clear by what mechanism mast cells interact with nerves/tenocytes and how the functionality of mast cells depends on glutamate binding and stimulation. In this review, we will address the role of different neuromediators-receptors especially glutamate/SP on mast cell function as well as summarize the possible mechanisms of the neuromediator-receptor axis on mast cells/nerves during healing, neurogenic inflammation, and pain responses in the context of in tissue injury.
Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular ... more Mast cells (MCs) are known to have a pathological impact in a variety of settings, in particular in allergic conditions. There is also limited evidence implicating MCs in diabetes, raising the possibility that MC function may be influenced by alterations in glucose levels. However, it is not known whether MCs are directly affected by elevated glucose concentrations. Moreover, it is not known which glucose transporters that are expressed by MCs, and whether MCs are dependent on glucose transporters for activation. Here we addressed these issues. We show that MCs express high levels of both glucose transporter 1 (GLUT1/Slc2A1) and GLUT3 (Slc2A3). Further, we show that the inhibition of either GLUT1 or GLUT3 dampens both MC degranulation and cytokine induction in response to IgE receptor crosslinking, and that combined GLUT1 and GLUT3 inhibition causes an even more pronounced inhibition of these parameters. In contrast, the inhibition of GLUT1 or GLUT3, or combined GLUT1 and GLUT3 inhibition, had less impact on the ability of the MCs to respond to activation via compound 48/80. Elevated glucose concentrations did not affect MC viability, and had no stimulatory effect on MC responses to either IgE receptor crosslinking or compound 48/80. Altogether, these findings reveal that MCs are strongly dependent on glucose transport via GLUT1 and/or GLUT3 for optimal responses towards IgE-mediated activation, whereas MC functionality is minimally affected by elevated glucose levels. Based on these findings, antagonists of GLUT1 and GLUT3 may be considered for therapeutic intervention in allergic conditions.
Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between... more Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.
Background: Both acute and chronic Achilles tendon ruptures are affected by alterations in the ex... more Background: Both acute and chronic Achilles tendon ruptures are affected by alterations in the extracellular matrix during the healing process of the tendon. Yet, these alterations in gene expression patterns are not well characterized. Purpose: To characterize temporal and spatial differences in gene expression patterns after an Achilles tendon rupture and to evaluate if cells from chronic Achilles tendon ruptures have the same ability to form new tendon tissue (tendon constructs) as healthy tendon cells. Study Design: Controlled laboratory study. Methods: A total of 35 patients with surgically treated Achilles tendon ruptures were included in the study and divided into 3 groups: acute (\4 weeks), short-term chronic (1-6 months), and long-term chronic (.6 months). Biopsy specimens were collected during surgical repair and were used to analyze the gene expression within the different groups and to compare mRNA levels in the proximal and distal tendon ends. A complementary in vitro experiment was performed to evaluate if cells from chronic Achilles tendon ruptures can form tendon constructs. Results: The mRNA levels for COL1A1 and COL3A1 were significantly higher in the short-term chronic group compared with the acute group (P \ .05). Both MMP-1 and MMP-13 had the highest mRNA levels in the acute group (P \ .01) compared with the long-term chronic group, while MMP-2 had the highest mRNA level in the short-term chronic group. Significant differences between the proximal and distal tendon ends were only detected for the monocyte and macrophage marker CD163 (P \ .05), which was more expressed proximally. Cells extracted from chronic Achilles tendon ruptures displayed a similar ability and effectiveness to form tendon constructs as healthy tendon cells. Conclusion: A high collagenase gene activity after an Achilles tendon rupture indicated possible rapid matrix degradation in the acute phase. Chronic ruptures appeared to initiate the healing process even before treatment, indicated by the higher expression of collagen in the short-term chronic group. Cells from chronic Achilles tendon ruptures also displayed an ability to form new tendon tissue in vitro. Clinical Relevance: The study shows a rapid increase in collagenase gene expression, which could lead to matrix degradation that continues for months after an Achilles tendon rupture.
Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdo... more Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdown of gingival tissue, the periodontal ligament, and alveolar bone, leading ultimately to tooth loss. We previously reported the pleckstrin gene (PLEK) to be highly upregulated in gingival tissue of patients with CP and the only gene concurrently upregulated in other inflammatory diseases including rheumatoid arthritis and cardiovascular diseases. Using saliva from 169 individuals diagnosed with CP and healthy controls, we investigated whether pleckstrin could serve as a novel biomarker of periodontitis. Additionally, we explored signal pathways involved in the regulation of PLEK using human gingival fibroblasts (HGFs). Pleckstrin levels were significantly higher (p < 0.001) in the saliva samples of patients with CP compared to controls and closely associated with CP severity. Immunohistochemical analysis revealed the expression of pleckstrin in inflammatory cells and gingival fibroblasts of CP patients. To explore the signal pathways involved in pleckstrin regulation, we stimulated HGFs with either interleukin-1β (IL-1β) or lipopolysaccharides (LPS) alone, or in combination with inhibitors targeting c-Jun N-terminal kinase, tyrosine kinase, protein kinase C, or p38 MAP kinase. Results showed that IL-1β and LPS significantly increased PLEK mRNA and pleckstrin protein levels. VX-745, the p38 MAP kinase inhibitor significantly decreased IL-1β- and LPS-induced pleckstrin levels at both the mRNA and the protein level. Together, these findings show that pleckstrin could serve as a salivary biomarker for the chronic inflammatory disease periodontitis and a regulator of inflammation via the p38 MAP kinase pathway.
Mast cells are emerging as players in the communication between peripheral nerve endings and cell... more Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon h... more Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon homeostasis/pain after tissue damage is crucial in developing novel therapeutics for human tendon disorders. The inflammatory mechanisms that are operative in response to tendon injury are not fully understood, but it has been suggested that inflammation occurring in response to nerve signaling, i.e., neurogenic inflammation, has a pathogenic role. The mechanisms driving such neurogenic inflammation are presently not clear. However, it has recently been demonstrated that mast cells present within the injured tendon can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling and thereby modulate neurogenic inflammation following tissue injury. In this review, we discuss the role of mast cells in the communication with peripheral nerves, and their emerging role in tendon healing and inflammation after injury.
Objectives Management of chronic tendon pain is difficult and controversial. This is due to poor ... more Objectives Management of chronic tendon pain is difficult and controversial. This is due to poor knowledge of the underlying pathophysiology of chronic tendon pain, priorly known as tendinitis but now termed tendinopathy. The objective of this topical review was to synthesize evolving information of mechanisms in tendon pain, using a comprehensive search of the available literature on this topic. Content This review found no correlations between tendon degeneration, collagen separation or neovascularization and chronic tendon pain. The synthesis demonstrated that chronic tendon pain, however, is characterized by excessive nerve sprouting with ingrowth in the tendon proper, which corresponds to alterations oberserved also in other connective tissues of chronic pain conditions. Healthy, painfree tendons are devoid of nerve fibers in the tendon proper, while innervation is confined to tendon surrounding structures, such as sheaths. Chronic painful tendons exhibit elevated amounts of pa...
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's d... more Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by motor symptoms, such as rigidity, resting tremor, and bradykinesia, mainly caused by the progressive death of midbrain dopaminergic neurons in the nigrostriatal cells. Accumulating evidence indicates that PD is also accompanied by a wide range (50% of PD patients) of non-motor symptoms (NMS) including sleep disturbances, and neuropsychiatric and cognitive deficits. These symptoms often appear in the early, pre-motor stage of the disease, when the dopaminergic degeneration is still partial. The pathophysiology of NMS in PD is still a matter of debate and, as a consequence, an efficient therapy has not yet been identified. For these reasons, the preclinical research on PD is nowadays particularly focused on the development of new animal models for the study of the biological correlates of these symptoms. To investigate the NMS of PD, we produced a mouse model characterized by partial depletion of the nigrostriatal dopaminergic system. For this purpose, we subjected C57BL/6J mice to a bilateral injection of 6-hydroxy dopamine into the dorsal striatum. The efficacy of the surgery was verified by western blotting quantification of the remaining tyrosine hydroxylase in the striatum of mice. Nonetheless, the lesioned and control mice were tested with behavioral tasks commonly used to evaluate depression and anxiety in mice. We showed that the lesion produces in mice an anxiety-and depression-like phenotype. Moreover, we found that these deficits were insensitive to L-DOPA, the most common drug used to treat motor symptoms in PD patients. Conversely, both anxiety and depression were reverted in our mouse model, by the administration of the selective dopaminergic D2 receptor agonist Pramipexole. Interestingly, we also found that Citalopram and Reboxetine, serotonin and noradrenaline transporter inhibitors respectively, fully restored the behavior of lesioned mice. Importantly, these data are in line with clinical observations that report a therapeutic effect of these drugs on anxiety and depression in PD patients.
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA, 2017
Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles te... more Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing. One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were l...
Whether neuromediator displays a pathway of signaling to mast cells has been mysterious until rec... more Whether neuromediator displays a pathway of signaling to mast cells has been mysterious until recently when the expression of glutamate receptors on mast cells was established by both in-vivo and in-vitro studies. We recently demonstrated that exposure of mouse mast cells to neuromediator (e.g., glutamate) activates a broad range of glutamate receptors, of both ionotropic and metabotropic types. Our earlier studies also indicate that mouse mast cells may respond to glutamate receptor antagonists. It was further observed that the exposure of mast cells to glutamate resulted in an increased level of pro-inflammatory cytokines/chemokines and transcriptional response, introducing the concept of a glutamate-glutamate receptor axis in mast cells, which can contribute to neuroinflammation and pain regulation in peripheral soft tissues (e.g., tendon). Different neuromediator including glutamate, Substance P, and calcitonin generelated peptide (CGRP) have the excitatory response both in the peripheral and central nervous system and have been implicated in various diseases including pain, neurogenic inflammation, and cancer. Optimal neuromediators response is crucial for the body but in excess, however, it is harmful and causes many disorders including neuronal death through a massive calcium influx via its specific (e.g., glutamate via ionotropic and/or metabotropic) receptors. The glutamate-glutamate receptor axis in mast cells is exclusive. However, mast cells are emerging players in the communication between peripheral nerve endings and the immune system. It is not so clear by what mechanism mast cells interact with nerves/tenocytes and how the functionality of mast cells depends on glutamate binding and stimulation. In this review, we will address the role of different neuromediators-receptors especially glutamate/SP on mast cell function as well as summarize the possible mechanisms of the neuromediator-receptor axis on mast cells/nerves during healing, neurogenic inflammation, and pain responses in the context of in tissue injury.
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Papers by Dr. Md. Abdul Alim